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Thermogenesis and insulin sensitivity

Thermogenesis and insulin sensitivity

All the experiments were conducted by using Thermogenssis adipocytes 7 days after differentiation. Search Search articles by subject, keyword or author. Books ShopDiabetes.

Christian Benedict sensltivity, Swantje BredeHelgi B. SchiöthHendrik Lehnert Citrus bioflavonoids and fertility, Bernd SchultesJan BornManfred Hallschmid; Intranasal Insulin Enhances Postprandial Thermogenesis and Lowers Postprandial Serum Insulin Levels in Healthy Men.

Diabetes 1 Citrus bioflavonoids and fertility ; 60 Thermotenesis : — Animal studies indicate a prominent role of sesitivity insulin signaling in the senwitivity of peripheral energy metabolism. We determined the effect of sensiyivity insulin, which directly targets the brain, on glucose metabolism and Thermogenesiis expenditure Thermogenwsis humans.

In a double-blind, placebo-controlled, balanced within-subject comparison, 19 healthy normal-weight men Therogenesis years old were intranasally administered IU Ideal body composition insulin after an overnight fast.

Sensittivity expenditure assessed via indirect calorimetry and blood concentrations of glucose, insulin, Sensitivtiy, and free fatty acids FFAs were measured before and after insulin administration and the subsequent consumption of a high-calorie liquid meal of kcal, Thermogenesis and insulin sensitivity.

Intranasal insulin, compared Wild salmon cooking methods placebo, increased postprandial energy expenditure, i.

Intranasal insulin also induced a transient decrease in anc serum FFA levels. Enhancing brain sensitivitj signaling by sensitifity of intranasal Thwrmogenesis administration enhances the acute thermoregulatory and glucoregulatory response to food sensitiviyt, suggesting that central nervous insulin contributes sensittivity the control Thermogenesis and insulin sensitivity Thermogenwsis energy homeostasis in humans.

Animal studies have yielded evidence that the regulation of whole-body energy flux critically Thermogenesis and insulin sensitivity on intact brain insulin signaling 1 insuin, 2. Most recent findings have shown that the hypothalamic administration of insulin increases brown adipose Holistic mood support thermogenesis sensitvity direct inhibitory effects on warm-sensitive neurons 3.

Insulln, studies in rodents have jnsulin that in addition to its direct inhibitory effect on hepatic gluconeogenesis, Tehrmogenesis acts in the hypothalamus insulln decrease glucose production in the liver 45thus establishing an insulin-driven brain-liver axis that controls Termogenesis glucose homeostasis.

Insupin examined whether insulin acting in the human brain exerts comparable effects ibsulin energy sensitiivity by administering intranasal Prebiotics for improved gut barrier function that bypasses the blood-brain barrier and reaches the insulinn compartment along the olfactory nerve 67 imsulin, modulating central nervous functions in the absence of relevant peripheral effects 8.

Notably, intranasal insulin sensiitivity food Therrmogenesis 9 and body fat content 10 Thermogenesis and insulin sensitivity Tyermogenesis men, indicating Raspberry lemonade recovery drink following sensitviity administration, the hormone accesses neuronal networks relevant for energy sensiticity.

Against Energy enhancing tips background, in the present Thermmogenesis we assessed the effects of intranasal insulin on the glucoregulatory ibsulin thermoregulatory response sensitiivty food intake xensitivity humans.

Nineteen healthy men mean ± SEM age They gave written informed consent to Muscle growth mindset study, which conformed to the Isulin of Citrus bioflavonoids and fertility and was approved by the innsulin ethics xensitivity.

Each subject participated in two conditions insulin and placebo spaced apart by at least Thermigenesis weeks. The order Citrus bioflavonoids and fertility conditions was balanced across subjects. Body weight seensitivity body composition BIA M; Data Input, Frankfurt, Thrmogenesis did not differ between conditions.

After a h fast, experimental sessions started at a. with baseline assessments of energy expenditure ineulin blood parameters Fig.

Throughout the experiment, subjects rested in bed in a supine position in a quiet room of constant temperature 23°C. At a. Insulin and placebo were administered sensittivity precision air Sensitivoty Aero Pump, Hochheim, Germany that fill the nostrils and the nasal cavity with aerosol, thus enabling the solution to effectively target the olfactory epithelium.

The dose of intranasal insulin used here has previously been shown anc be functionally Berry Health Benefits in healthy humans 9 Experimental schedule.

Nineteen healthy subjects who had fasted overnight spent the experimental day anf in bed in a supine position. Measurements of energy Thetmogenesis by min periods of indirect Thetmogenesis were performed during baseline — sdnsitivity. Blood samplings for the determination sensitigity plasma glucose, serum insulin, C-peptide, and free fatty acids Thermogenesis and insulin sensitivity are indicated by syringe symbols.

Calorimetric measurements took place inaulin to a. baselinefrom Thermogeneiss a. to assess effects of intranasal insulin aloneand Thermogenseis times between and p. The rise in energy expenditure sensitiviyt the Obesity and long-term effects state baseline measurement from aensitivity a.

and the postprandial state Thermogenwsis energy expenditure from Cayenne pepper for blood pressure p. reflects diet-induced thermogenesis, i. Postprandial measurements were separated by min breaks during which the ventilation hood was not worn but the subjects remained in bed.

For the assessment of plasma glucose levels and serum concentrations of insulin, C-peptide, and free fatty acids FFAsblood was sampled twice during baseline and a. with a final sample taken at p.

Plasma glucose levels were measured in fluoride plasma hexokinase method, Aeroset; Abbott Diagnostics, North Chicago, IL. Serum concentrations of insulin and C-peptide were measured by an Immulite analyzer Siemens Medical Solutions Diagnostics, Los Angeles, CA.

FFA concentrations were measured by enzymatic assays as previously described Data are presented as means ± SEM. Statistical analyses were based on ANOVA including the repeated-measures factors condition and time referring to the immediate posttreatment and postprandial periods. Postprandial glucose and hormone concentrations a.

were expressed as areas under the curve AUCs calculated according to the trapezoidal rule. Post hoc two-sided t tests were used for single time point comparisons.

Intranasal insulin enhances postprandial energy expenditure. The rise in energy expenditure between baseline — a. and the postprandial state a. reflects the energy emitted mainly as heat during food metabolization diet-induced thermogenesis [DIT] right panel.

Immediately after intranasal insulin administration, i. placebo 4. placebo 1, ± 23 vs. In parallel with the slight postinsulin administration drop in plasma glucose, a small increase in serum insulin insulin vs. placebo Following liquid food intake, the postprandial increase in both insulin and C-peptide concentrations was reduced by intranasal insulin in comparison with placebo AUC, a.

Intranasal insulin lowers postprandial serum insulin levels. Concentrations of plasma glucose Aserum insulin Bserum C-peptide Cand serum free fatty acids D before and after acute intranasal administration nose symbol of intranasal insulin IU; solid lines and black bars and placebo dashed lines and white bars followed by the standardized ingestion of kcal of liquid food cup symbol.

Postprandial levels a. were also expressed as AUCs right panels. All values are presented as means ± SEM. We demonstrated in humans that acutely enhancing brain insulin signaling by intranasal administration of the hormone increases postprandial thermogenesis. The parallel treatment-induced reduction in postprandial serum insulin concentrations while plasma glucose levels were comparable between conditions indicates that following intranasal insulin administration to the brain, lower circulating levels of the hormone are sufficient to dispose of meal-related increases in plasma glucose.

In line with findings in animals 4513our results support the notion that brain insulin signaling in humans is involved in the control of whole-body energy homeostasis.

In keeping with previous experiments 911intranasal administration of IU insulin induced a transient and mild increase in serum insulin concentrations accompanied by a slight drop in prefood intake plasma glucose that clearly remained within the euglycemic range.

Due to the relatively high dose administered here compared with that in previous studies 68a small ratio of the hormone may have entered the circulation via the nasal mucosa.

However, the transient nature and limited size of these immediate effects argues against an involvement of systemic uptake of intranasal insulin in its impact on postprandial thermogenesis and glucose metabolism. This conclusion is corroborated by the fact that immediate and postprandial effects were not statistically related.

The balanced regulation of nutrient intake and energy expenditure relies on the hypothalamus as a major integrator of nutritional and hormonal signals from the body periphery, including glucose and insulin 1.

Direct injections of insulin into the preoptic area of the hypothalamus induce a dose-dependent increase in core body temperature due to stimulation of brown adipose tissue thermogenesis that is assumed to be mediated by inhibitory insulinergic action on warm-sensitive hypothalamic neurons 3.

In our experiments, intranasal administration of the hormone to the brain did not affect resting energy expenditure but evoked a distinct increase in postprandial thermogenesis. Increased postprandial energy expenditure due to enhanced brain insulin signaling adds to the reduction in food intake previously observed after intranasal administration of the hormone 9suggesting that the catabolic impact of central nervous insulin 1014 is mediated not only by anorexigenic but also by thermogenic effects of the hormone.

Still, further studies on this issue are needed and should include measurements of body temperature, brown adipose tissue activity, and relevant vital signs like heart rate and blood pressure to elucidate the effect of brain insulin signaling on energy expenditure in humans.

A most remarkable finding of our study is the intranasal insulin—induced reduction in postprandial serum insulin concentrations while the food intake-induced rise in plasma glucose remained unaffected, suggesting that intranasal insulin improves postprandial insulin sensitivity.

A regulatory effect of central nervous insulin on hepatic glucose metabolism has been indicated by animal studies showing that a selective decrease in hypothalamic insulin receptors reduces hepatic insulin sensitivity and results in marked increases in hepatic glucose production in the presence of plasma insulin concentrations equaling those of control animals This pattern suggests that enhancing brain insulin signaling by intranasal administration of the hormone may act on glucose homeostasis in the body periphery by supporting hepatic insulin action.

Nevertheless, given that postprandial liver glucose production accounts for approximately one-fifth to one-half of fasting values 17improved insulin-dependent metabolization of ingested glucose may also have contributed to the intranasal insulin-induced decrease in postprandial serum insulin levels.

Such an effect could basically be supported by the observed decrease in prandial FFA levels due to intranasal insulin inasmuch as FFAs are known to impair insulin-stimulated muscle uptake of glucose However, FFA effects on peripheral insulin-stimulated glucose uptake slowly develop over some hours 19which, in conjunction with the lack of a significant correlation between the decreases in prandial FFA and postprandial insulin concentrations, makes this view unlikely.

Furthermore, a contribution of enhanced noninsulin-mediated glucose disposal, i. Although the present results suggest that insulin administration to the human brain enhances the efficiency of the glucoregulatory brain-liver axis in response to nutrient intake, our observations should be corroborated in future studies that rely on more refined measurements of insulin sensitivity, e.

It is also noteworthy that most recent animal data hint at divergent effects of hypothalamic insulinergic signaling on peripheral glucose homeostasis and energy expenditure depending on the involvement of agouti-related protein or proopiomelanocortin neuronal pathways In this regard, general enhancements in brain insulin signaling as performed in our study do not permit differentiations.

Taken together, our findings indicate that intranasal insulin acutely increases postprandial thermogenesis and improves the glucoregulatory response to food intake, suggesting that boosting brain insulin signaling in humans enhances the body's ability to cope with calorie consumption 20 Against the background of studies indicating that obesity and peripheral insulin resistance are associated with reduced central nervous insulin sensitivity 22— 24enhancing brain insulin signaling may emerge as a useful approach in the therapeutic management of disorders hallmarked by disturbed glucose homeostasis The costs of publication of this article were defrayed in part by the payment of page charges.

Section solely to indicate this fact. The funding sources had no input in the design and conduct of this study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

Aero Pump, Hochheim, Germany, generously provided us with precision nasal air pumps. No other potential conflicts of interest relevant to this article were reported. designed the study, analyzed the data, contributed to writing the manuscript, and collected data or performed experiments for the study.

enrolled patients and collected data or performed experiments for the study. contributed to writing the manuscript. designed the study, analyzed the data, and contributed to writing the manuscript. All authors had full access to all of the data and take responsibility for the integrity and accuracy of the data analysis.

We thank I. von Lützau, M.

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Subject Area: Endocrinology , Further Areas , Gastroenterology , General Medicine , Immunology and Allergy , Nephrology , Ophthalmology , Pneumology , Women's and Children's Health. Book Series: Frontiers in Diabetes. Publication date:. Chapter Navigation. Book Chapter. Macor C. Institute of Semeiotica Medica, Patologia Medica III, University of Padua, Italy.

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Onset of Thermogenesis in Response to Cold in Newborn Mice. Karger International S. Karger AG P.

JCI - Brown adipose tissue regulates glucose homeostasis and insulin sensitivity

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Digital Version Pay-Per-View Access. BUY THIS Chapter. Print Version. Buy Token. Related Topics thermogenesi. Email alerts Latest Book Alert.

Related Book Content Pathophysiology of Insulin Resistance in Small for Gestational Age Subjects: A Role for Adipose Tissue?

Interactions between the Gut, the Brain and Brown Adipose Tissue Function. Gut Decontamination with Norfloxacin and Ampicillin Enhances Insulin Sensitivity in Mice.

Androgens and Severe Insulin Resistance States: Basic and Clinical Aspects. Influence of Maternal Vitamin B 12 and Folate on Growth and Insulin Resistance in the Offspring.

Human Congenital Perilipin Deficiency and Insulin Resistance. Syndromes Associated with Mutations in the Insulin Signalling Pathway. The Emergence of Adipocytes.

Downstream Insulin-Like Growth Factor. Diabetes and Hyperthyroidism. Related Articles Regulation of Fat Storage via Suppressed Thermogenesis: A Thrifty Phenotype That Predisposes Individuals with Catch-Up Growth to Insulin Resistance and Obesity.

Thermogenesis Induced by Nutrient Administration in Man. Does Prolonged Exercise Alter Diet-Induced Thermogenesis? Genetic and Dietary Influences on the Levels of Diet-Induced Thermogenesis and Energy Balance in Adult Mice.

Brown Adipose Tissue Thermogenesis during Pregnancy in Mice. Contribution of Brown Fat to the Neonatal Thermogenesis. Neuropeptidergic Mediators of Spontaneous Physical Activity and Non-Exercise Activity Thermogenesis.

Influence of Changes in Body Composition and Adaptive Thermogenesis on the Difference between Measured and Predicted Weight Loss in Obese Women. Postprandial Thermogenesis in Leanness and Anorexia Nervosa.

Onset of Thermogenesis in Response to Cold in Newborn Mice. Karger International S. Karger AG P. O Box, CH Basel Switzerland Allschwilerstrasse 10, CH Basel.

Facebook LinkedIn X YouTube WeChat Experience Blog. Privacy Policy Terms of Use Imprint Cookies © S. Karger AG, Basel. The corollary is that acclimated BAT could be serving beneficial metabolic functions not related to temperature regulation per se.

Third, newly identified cytokines, such as FGF21, may mediate temperature-acclimated tissue cross-talk. Recent identification of a FGFadiponectin feed-forward axis 41 led us to wonder whether FGF21 augmentation after cold acclimation could have brought forth the adiponectin rise.

When BAT was muted at the end of warm acclimation and adiponectin dwindled, FGF21 did not fall, suggesting that non-BAT FGF-secreting tissues might have compensated in states of relative BAT deficiency.

Fourth, although we did not observe an increase in beige fat gene expression, possibly due to the small sample size, we speculate fat browning to be a possibility.

This is corroborated by finding an increased expression of the BAT gene CIDEA in adipose tissue after cold acclimation. Compared with WAT, BAT has relatively less lipid, as it is filled with abundant mitochondria and blood vessels.

This is exemplified by water-fat separated magnetic resonance imaging revealing a lower fat fraction in activated BAT both in humans 42 and in rodents This is also supported by previous studies demonstrating cell-autonomous 44 and endocrine-mediated 19 cold-induced WAT browning in humans.

Further studies are required to ascertain whether WAT browning contributes to cold-acclimated BAT-induced metabolic changes. Most importantly, all these changes occurred in the absence of measureable EE, caloric intake, or body compositional alterations, suggesting such responses to be primary cold-induced metabolic sequelae rather than compensatory physiologic adaptations.

Nonetheless, because the desire to eat heightened after cold acclimation, we cannot exclude the possibility that appetite stimulation could diminish metabolic benefits of BAT recruitment if it increases caloric intake in longer-term studies. The inducibility, suppressibility, and plasticity of human BAT entail implications beyond thermoregulatory physiology.

The translation of recently discovered BAT activators in the laboratory to pharmacologic BAT stimulants available for clinical use is not a trivial process Our study substantiates, in contrast, a simple BAT-modulating strategy: a mild reduction in environmental temperature is capable of recruiting BAT and yielding associated metabolic benefits; conversely, even a small elevation in ambient temperature could impair BAT and dampen previously attained metabolic benefits.

Such reversible metabolic switching, occurring within a temperature range achievable in climate-controlled buildings, therefore carries therapeutic implications of BAT acclimation both on an individual and a public health level.

Bedroom temperature has gradually increased from 19°C to The blunting of BAT function due to widespread use of indoor climate control could be a neglected contribution to the obesity epidemic.

Moderate downward adjustment of indoor temperature could represent a simple and plausible strategy in dampening the escalation of obesity on a population level. Our volunteers reported satisfactory sleep during acclimation, although more formal assessment of sleep quality is required in future studies.

Our findings should be viewed as a proof of concept illustrating human BAT plasticity. We acknowledge the small sample size to be a limitation of our study. Unfortunately, the conduct of long-term acclimation study necessitated substantial resources and regrettably prohibited a large sample size.

The unveiled positive relation between acclimated BAT and glucose homeostasis is clinically relevant.

Glucose intolerance is an independent risk factor of cardiovascular mortality, and postprandial hyperglycemia is its earliest manifestation We emphasize that a causal linkage could not be definitely ascertained between BAT recruitment and postprandial insulin sensitivity improvement; however, our study provides compelling circumstantial evidence supporting a potential therapeutic role of BAT in impaired glucose metabolism and calls for the investigation of similar temperature acclimation in individuals with impaired glycemia.

Our observation of BAT recruitment accompanied by insulin sensitization in the absence of significant weight loss echoes animal findings showing glucose homeostasis improvement after fat browning to be greater than expected from adiposity reduction alone 49 , In summary, temperature acclimation modulates BAT abundance and activity, subsequently impacting energy and substrate metabolism in humans.

BAT exhibits thermal plasticity intimately related to glucose homeostasis. Harnessing BAT by simple adjustment of ambient temperature could be a new strategy in the combat against obesity, diabetes, and related disorders. Clinical trial reg.

NCT, clinicaltrials. The authors thank Dr. Peter Herscovitch and Dr. This study was supported by the Intramural Research Program ZDK of NIDDK and the NIH Clinical Center. was supported by an Australian National Health and Medical Research Council Early Career Fellowship, the Diabetes Australia Fellowship and Bushell Travelling Fellowship, and the School of Medicine, University of Queensland.

The funders had no role in the design or conduct of the study; collection, management, analysis, or interpretation of data; or preparation, review, or approval of the manuscript. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions.

participated in the development of the study concept and design, research, acquisition of data, and analysis and discussion of results; wrote the manuscript; participated in critical revision; and approved the final version of the manuscript. participated in the development of the study concept and design, research, acquisition of data and analysis and discussion of results; participated in critical revision; and approved the final version of the manuscript.

and C. researched and analyzed data, contributed to discussion of results, participated in critical revision, and approved the final version of the manuscript. and F. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

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Volume 63, Issue Previous Article Next Article. Research Design and Methods. Article Information. Article Navigation. Metabolism October 13 Temperature-Acclimated Brown Adipose Tissue Modulates Insulin Sensitivity in Humans Paul Lee ; Paul Lee.

This Site. Google Scholar. Sheila Smith ; Sheila Smith. Joyce Linderman ; Joyce Linderman. Amber B. Courville ; Amber B. Robert J. Brychta ; Robert J. William Dieckmann ; William Dieckmann. Charlotte D. Werner ; Charlotte D. Kong Y. Chen ; Kong Y.

Francesco S. Celi Francesco S. Corresponding author: Francesco S. Celi, fsceli vcu. Diabetes ;63 11 — Article history Received:. Get Permissions. toolbar search Search Dropdown Menu. toolbar search search input Search input auto suggest.

Month 1: 24°C. Month 2: 19°C. Month 3: 24°C. Month 4: 27°C. P trend. View Large. Table 2 Physiologic parameters across 4 months of acclimation. Total EE kcal 2, ± 2, ± a 2, ± 2, ± a 2, ± 2, ± a 2, ± 2, ± a 0. Table 3 Nutritional and body compositional parameters across 4 months of acclimation.

Table 4 Hormonal and metabolic parameters across 4 months of acclimation. Figure 1. View large Download slide. Figure 2. Figure 3. Figure 4. Putative contributors to the secular increase in obesity: exploring the roads less traveled. Search ADS.

Brown adipose tissue as a regulator of energy expenditure and body fat in humans. Thermogenically competent nonadrenergic recruitment in brown preadipocytes by a PPARgamma agonist. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis.

Mitochondria of adult human brown adipose tissue contain a 32 Mr uncoupling protein. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. van Marken Lichtenbelt. Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans.

Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Brown fat activation mediates cold-induced thermogenesis in adult humans in response to a mild decrease in ambient temperature. van der Lans. Cold acclimation recruits human brown fat and increases nonshivering thermogenesis.

Human brown adipose tissue: regulation and anti-obesity potential [Review]. A critical appraisal of the prevalence and metabolic significance of brown adipose tissue in adult humans. Impact of brown adipose tissue on body fatness and glucose metabolism in healthy humans.

UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Minimal changes in environmental temperature result in a significant increase in energy expenditure and changes in the hormonal homeostasis in healthy adults.

Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans.

Mild cold exposure modulates fibroblast growth factor 21 FGF21 diurnal rhythm in humans: relationship between FGF21 levels, lipolysis, and cold-induced thermogenesis. Thyroid hormone induced brown adipose tissue and amelioration of diabetes in a patient with extreme insulin resistance.

Thyroid hyperactivity with high thyroglobulin in serum despite sufficient iodine intake in chronic cold adaptation in an Arctic Inuit hunter population. Different metabolic responses of human brown adipose tissue to activation by cold and insulin. An FGFadiponectin-ceramide axis controls energy expenditure and insulin action in mice.

MRI detection of brown adipose tissue with low fat content in newborns with hypothermia. A human-specific role of cell death-inducing DFFA DNA fragmentation factor-alpha -like effector A CIDEA in adipocyte lipolysis and obesity.

Cidea controls lipid droplet fusion and lipid storage in brown and white adipose tissue. Could increased time spent in a thermal comfort zone contribute to population increases in obesity. Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria.

The DECODE study group. European Diabetes Epidemiology Group. Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe.

Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

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Insulin and thermogenesis

Effect of low-dose hypothalamic TNFα on leptin action and neurotransmitter expression. Spontaneous food intake A was determined over 12 h. Signal transduction through JAK2 phospho-JAK2, P-JAK B and STAT3 phospho-STAT3, P-STAT3 C , and the expression of SOCS3 D were evaluated by immunoblot.

control and vs. CART, Cocaine and amphetamine-related transcript; MCH, melanin-concentrating hormone; NPY, neuropeptide Y. BAT and skeletal muscle are the effectors of most of the thermogenic activity in rodents 19 , The icv injection of low-dose TNFα produces significant reductions in the expressions of UCP1, cytochrome c , PGC-1α, and Dio2 in BAT Fig.

In addition, hypothalamic TNFα reduces mitochondria respiration in isolated muscle fibers Fig. Moreover, hypothalamic TNFα exerts no effect on the blood levels of the thyroid hormones T3 Fig.

Effect of low-dose hypothalamic TNFα on thermogenesis. UCP1 and PGC1α were measured by immunoblot A and real-time PCR B , whereas Dio2 was measured only by real-time PCR C. O 2 consumption was evaluated by an isolated skeletal muscle fiber respirometric assay D.

The expression of cytochrome c Cyt C and SERCA1 was measured by immunoblot E. Citrate synthase activity in skeletal muscle was measured by spectrophotometry F.

Serum levels of T3 G and T4 H were measured by RIA. To evaluate the systemic outcomes of a low-grade hypothalamic inflammation, rats were icv treated with a low-dose of TNFα, and insulin secretion and action in peripheral tissues were determined.

The blood level of insulin Fig. However, upon glucose stimulation the ratio insulin secretion in Moreover, upon hypothalamic TNFα treatment, insulin signal transduction through IRS1 and FOXO1 is significantly impaired in liver Fig. Effect of low-dose hypothalamic TNFα on insulin secretion and action.

Serum insulin levels were determined by RIA A. Insulin secretion by isolated pancreatic islets was evaluated in islets exposed to 2. An index of pancreatic islet responsiveness to glucose was obtained by the ratio of secretion in Samples of liver D and E and skeletal muscle F and G were employed for the determination of insulin-induced tyrosine phosphorylation of IRS1 D and F and serine phosphorylation of FOXO1 p-FOXO E and G.

IRS1 tyrosine phosphorylation was evaluated in total protein extracts submitted to immunoprecipitation IP with anti-IRS1 antibodies and immunoblot IB with anti-phosphotyrosine pY antibodies. Control and TNFα 2. Saturated fatty acids induce hypothalamic inflammation through the activation of TLR4 signaling and endoplasmic reticulum stress 4 , The icv injection of stearic acid C produces a dose-dependent increase of TNFα in the hypothalamus Fig.

In addition, icv stearic acid impairs insulin signal transduction through IRS1 and FOXO1 in liver Fig. The icv treatment with the anti-TNFα monoclonal antibody infliximab, reduces stearic acid-induced IL1β expression in the hypothalamus Fig.

Effects of stearic acid in the hypothalamus. Wistar rats were treated icv once a day for 4 d, with 2 μl saline Control , BSA, or stearic acid containing 90 μg, or the amount depicted in panel A.

TNFα protein expression was determined by immunoblot IB in total protein extracts from hypothalami A. O 2 consumption B and CO 2 production C were determined by respirometry. The same rats were employed for evaluations of UCP1 I and cytochrome C Cyt C J protein expressions by immunoblot in total protein extracts from BAT.

The systemic use of the anti-TNFα monoclonal antibody, infliximab, improves insulin signal transduction in peripheral tissues of diet-induced obese mice To determine the impact of TNFα and low-grade hypothalamic inflammation in systemic metabolic parameters, DIO rats were icv treated with infliximab, and markers of thermogenesis and insulin signal transduction were evaluated.

In addition, the expression of UCP1 in BAT is increased to levels similar to those of lean controls Fig. Interestingly, hypothalamic infliximab is also effective for improving insulin signal transduction through IRS1 in the liver Fig.

Upon prolonged infliximab icv treatment 8 d , a significant reduction of body mass gain is achieved Fig. Effect of inhibition of TNFα on the hypothalamus of obese rats. Lean [standard diet SD ] or diet-induced obese high-fat diet HFD Wistar rats were treated icv with saline or infliximab 0.

BAT was obtained for determination of UCP1 expression by immunoblot C. To explore the role of the main TNFα receptor type, TNFR1, in DIO-dependent defects in thermogenesis and insulin signaling, TNFR1-KO mice were submitted to a HF diet, and parameters of thermogenesis and insulin signal transduction were studied.

Chow-fed KO mice consume more oxygen than controls and, when fed on a HF diet, this is significantly increased Fig. No differences in CO 2 production and in blood T3 and T4 levels are detected among the groups Fig.

However, UCP1 expression in BAT is significantly increased in KO mice Fig. This is accompanied by improved insulin signal transduction through IRS1 and FOXO1 in liver Fig.

Outcomes of DIO in TNFR1-KO. Control and TNFR1-KO mice were fed either regular chow [standard diet SD and SD KO] or high-fat diet HFD and HFD KO for 8 wk and body mass variation A and cumulative food intake B were determined. O 2 consumption C or CO 2 production D were evaluated by respirometry.

The serum levels of T3 E and T4 F were measured by RIA. respective condition without insulin. Type 2 diabetes mellitus DM2 results from the complex combination of insulin resistance and defective pancreatic β-cell function Most subjects with DM2 are overweight, and obesity-related factors have been proposed as important determinants of the loss of glucose homeostasis.

As insulin resistance progresses, the pancreatic β-cell increases secretion to compensate for peripheral demand. This compensation may fail depending on the genetic background and on the presence of harmful factors such as inflammatory molecules produced by the adipose tissue and excessive circulating nutrients, such as fatty acids and sugars After the characterization of inflammation as an important mechanism inducing hypothalamic dysfunction in obesity, it was shown that targeting hypothalamic inflammation by distinct means produced beneficial effects in body mass and also in peripheral insulin action 4 , 6 , However, it was not clear whether these outcomes resulted only from body mass reduction or were a consequence of improved hypothalamic activity, acting in parallel with body mass change.

TNFα is one of the main inflammatory factors produced by the hypothalamus in response to dietary intervention 3 , 4. Both microglia and neurons can express this cytokine, which plays an important role in the induction of hypothalamic resistance to leptin and insulin 3.

Interestingly, hypothalamic inflammation may exert a paradoxical effect on energy metabolism. Although at high magnitude, such as in cancer and sepsis, it leads to catabolism, at a low level, as observed in obesity, it has the opposite effect In the first part of this study, we showed that the level of hypothalamic TNFα protein is significantly higher in tumor-bearing, compared with control rats.

In obese animals, TNFα levels are also higher than controls but significantly lower than tumor-bearing rats. In both cases, the increased levels of hypothalamic TNFα are accompanied by changes in feeding behavior, which are inhibited in tumor-bearing and increased in obese animals.

Moreover, icv injection of a high concentration of TNFα reproduces a number of phenotypic features of cachexia, whereas at a low concentration it is clearly anabolic. It is interesting to notice that the effects of TNFα change sharply when the dose is increased by only fold.

This is in pace with the small differences in the levels of TNFα when comparing obesity and cancer, as shown here and elsewhere 25 , Thus, it is attractive to propose that the inflammatory paradox of the hypothalamus is a result of a difference in the magnitude of the inflammatory process.

In the case of sepsis and cancer, most inflammatory factors are systemic and high, reaching the central nervous system via the bloodstream. In obesity, the systemic levels of inflammatory factors are increased, compared with lean subjects, but are considerably lower than in cachexia.

However, in DIO, cytokines are also produced in the hypothalamus 3 , 4 , and it is not yet known whether low-grade inflammation results only from the action of locally produced cytokines or from the combination of local and systemic inflammatory factors.

When obesity is induced by a Western diet, the hypothalamus is the first tissue to exhibit molecular resistance to insulin 5. This fact, taken together with the results of other studies that show an improvement in peripheral insulin resistance, after the inhibition of hypothalamic inflammation 6 , 21 , suggest that the diabetes-like phenotype can be induced by hypothalamic dysfunction.

To evaluate the isolated effect of low-grade hypothalamic inflammation on peripheral insulin action, lean rats were treated icv with a low dose of TNFα.

This treatment produced an impairment of leptin anorexigenic effect and defective leptin signaling through JAK2 and STAT3, accompanied by increased hypothalamic expression of SOCS3. All these outcomes are similar to the findings reported in a number of animal models of obesity 27 , In addition, hypothalamic TNFα led to reductions in POMC, TRH, and CRH, all of which are neurotransmitters with important thermogenic functions.

This was accompanied by the negative regulation of important players in BAT and skeletal muscle thermogenesis, as seen in animal models and humans with glucose intolerance or diabetes Next, we evaluated the outcomes of low-grade hypothalamic inflammation on insulin secretion and action.

In DM2, both the action and secretion of insulin become defective, and it is believed that hyperglycemia will develop only when both these functions emerge together 22 , A short-term treatment with low-dose TNFα in the hypothalamus had no effect on glucose levels data not shown.

However, hyperinsulinemia was evident, and defective insulin secretion by isolated pancreatic islets reproduced features commonly seen in diabetic subjects and experimental animals 31 , Moreover, the evaluation of insulin signal transduction in liver and muscle revealed a reduced insulin-induced activation of IRS1 and FOXO1, which is a molecular hallmark of insulin resistance seen in distinct animal models and humans with glucose intolerance or diabetes In DIO, saturated fatty acids induce inflammatory signal transduction in the hypothalamus by at least two distinct mechanisms: 1 activation of TLR4 4 , and; 2 activation of PKCτ When rats were treated with stearic acid icv, the expression of TNFα was induced in a dose-dependent manner.

This was accompanied by reduced consumption of O 2 production of CO 2 , reduced UCP1 expression in BAT and reduced insulin signal transduction through IRS1 and FOXO1 in the liver and muscle. Therefore, the icv treatment with stearic acid reproduces the effects of TNFα on peripheral parameters, reflecting thermogenesis and insulin action.

In this context, recent data have shown that nutrients, including fatty acids, can activate hypothalamic S6 kinase, leading to hepatic resistance to insulin action A recent study has shown that the knockout of the main TNFα receptor, TNFR1, protects against DIO by an increased thermogenesis 7.

We tested the hypothesis that the ability of low-grade hypothalamic inflammation to modulate peripheral insulin action may be intermediated by this receptor isotype.

For this, TNFR1-KO mice were fed on a HF diet and evaluated for insulin signal transduction in the liver and muscle. Indeed, insulin responsiveness was completely preserved in KO mice compared with their controls, strongly suggesting that most the action of TNFα in the hypothalamus was delivered by this receptor.

Because the KO mice employed were devoid of TNFR1 in the whole body, we designed an experiment to evaluate the specific action of TNFα in the hypothalamus; for this, HF diet-fed rats were treated icv with the anti-TNFα-neutralizing antibody, infliximab, and thermogenesis and insulin signaling in peripheral tissues were evaluated.

As expected, the hypothalamic immunoneutralization of TNFα in HF diet-fed rats completely restored defective thermogenesis and insulin signal transduction in liver and muscle.

We conclude that, in animal models of obesity, a low-grade hypothalamic inflammation takes place. This inflammatory response plays an important role in the local induction of resistance to leptin and insulin, which provides the neuroendocrine basis for the development of obesity. An important advance was obtained by linking hypothalamic inflammation with a defective insulin action and an effective thermogenesis in peripheral tissues.

In addition, the adverse modulation of insulin secretion was observed. Although we have not explored the mechanisms that effectively deliver the neural signal to the affected peripheral organs, it is tempting to propose that the modulation of the sympathetic tonus could be involved.

This work adds information to support a seminal role played by hypothalamic dysfunction in the genesis of glucose intolerance and DM2. We thank Dr. Conran, from the University of Campinas, for English grammar edition and Mr. Cruz, from the University of Campinas for technical assistance.

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo and Conselho Nacional de Desenvolvimento Científico e Tecnológico.

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It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Navbar Search Filter Endocrinology This issue Endocrine Society Journals Clinical Medicine Endocrinology and Diabetes Medicine and Health Books Journals Oxford Academic Mobile Enter search term Search.

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Journal Article. Low-Grade Hypothalamic Inflammation Leads to Defective Thermogenesis, Insulin Resistance, and Impaired Insulin Secretion.

Ana Paula Arruda , Ana Paula Arruda. Oxford Academic. Marciane Milanski. Andressa Coope. Adriana S. PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms. Cancer Cell 3 , — Hansen, J. Retinoblastoma protein functions as a molecular switch determining white versus brown adipocyte differentiation.

USA , — Shreiber, S. The estrogen-related receptorα ERRα functions in PPARγ coactivator 1α PGC-1α -induced mitochondrial biogenesis. Stiles, B. Liver-specific deletion of negative regulator PTEN results in fatty liver and insulin hypersensitivity.

Shimomura, I. Cell 6 , 77—86 Takahashi, M. Genomic structure and mutations in adipose-specific gene, adiponectin. Iwaki, M. Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors.

Diabetes 52 , — Tarutani, et al. Tissue-specific knockout of the mouse Pig-a gene reveals important roles for GPI-anchored proteins in skin development. USA 94 , — Miyawaki, K. Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Rossmeisl, M.

Expression of the uncoupling protein 1 from the aP2 gene promoter stimulates mitochondrial biogenesis in uniocular adipocytes in vivo. Maeda, N. Nishizawa, H. Musclin, a novel skeletal muscle-derived secretory factor.

Kashiwagi, A. The regulation of glucose transport by cAMP stimulators via three different mechanisms in rat and human adipocytes. Download references.

We thank Y. Matsuzawa and K. Sugihara for their encouragement, and K. Nishida, K. Oiki and S. Mizuno for technical assistance. This work was supported in part by grants from the Suzuken Memorial Foundation, The Nakajima Foundation, Kanae Foundation for Life and Socio-Medical Science, The Tokyo Biochemical Research Foundation, Takeda Medical Research Foundation, Uehara Memorial Foundation, Takeda Science Foundation, Novartis Foundation Japan for the Promotion of Science, The Cell Science Research Foundation, The Mochida Memorial Foundation for Medical and Pharmaceutical Research, a Grant-in-Aid from the Japan Medical Association, The Naito Foundation, a grant from the Japan Heart Foundation Research, Kato Memorial Bioscience Foundation, Japan Research Foundation for Clinical Pharmacology, a grant from the Ministry of Health, Labor and Welfare, Japan, and Grants-in-Aid from COE Research and Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

Department of Social and Environmental Medicine, Graduate School of Frontier Bioscience, Osaka University, Yamadaoka, Suita, , Osaka. Department of Medicine and Pathophysiology, Graduate School of Frontier Bioscience, Osaka University, Yamadaoka, Suita, , Osaka.

Division of Food Science and Biotechnology, Laboratory of Nutrition Chemistry, Graduate School of Agriculture, Kyoto University, Kitashirakawa, Sakyo-ku, , Kyoto. Department of Dermatology, Osaka University, Yamadaoka, Suita, , Osaka. Department of Biochemistry, Akita University, Hondou, Akita, , Akita, Japan.

Advanced Medical Discovery Institute, University of Toronto, Toronto, M5G 2Cl, Ontario, Canada. Department of Pathology, Graduate School of Medicine, Osaka University, Yamadaoka, Suita, , Osaka. Center for Advanced Science and Innovation, Osaka University, Yamadaoka, Suita, , Osaka.

Department of Internal Medicine and Molecular Science, Osaka University, Yamadaoka, Suita, , Osaka. PREST, Japan Science and Technology Agency, Honcho, Kawaguchi, , Saitama, Japan. You can also search for this author in PubMed Google Scholar.

Correspondence to Iichiro Shimomura. Expression analyses of Cre in Adiponectin promoter-driven Cre transgenic mice. PDF 34 kb. Reprints and permissions. Komazawa, N. Enhanced insulin sensitivity, energy expenditure and thermogenesis in adipose-specific Pten suppression in mice.

Nat Med 10 , — Download citation. Received : 24 June Accepted : 08 September Published : 17 October Issue Date : 01 November Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article.

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Access through your institution. Buy or subscribe. Change institution. Learn more. Figure 2: Characteristics of adipose-specific Pten-deficient mice.

Figure 3: Increased thermogenesis and energy expenditure with adipose mitochondrial hypergeneration in AdipoPten-KO mice. Figure 4: Protein and mRNA analyses of Pten-deficient adipose tissues.

Figure 5: Suppression of Pten in 3T3-L1 adipocytes, and in vivo regulation of adipose Pten. Figure 6. References Maehama, T. Article CAS Google Scholar Jiang, G. Article CAS Google Scholar Whiteman, E. Article CAS Google Scholar Suzuki, A.

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Thermogenesis and insulin sensitivity -

reflects diet-induced thermogenesis, i. Postprandial measurements were separated by min breaks during which the ventilation hood was not worn but the subjects remained in bed.

For the assessment of plasma glucose levels and serum concentrations of insulin, C-peptide, and free fatty acids FFAs , blood was sampled twice during baseline and a. with a final sample taken at p. Plasma glucose levels were measured in fluoride plasma hexokinase method, Aeroset; Abbott Diagnostics, North Chicago, IL.

Serum concentrations of insulin and C-peptide were measured by an Immulite analyzer Siemens Medical Solutions Diagnostics, Los Angeles, CA.

FFA concentrations were measured by enzymatic assays as previously described Data are presented as means ± SEM. Statistical analyses were based on ANOVA including the repeated-measures factors condition and time referring to the immediate posttreatment and postprandial periods.

Postprandial glucose and hormone concentrations a. were expressed as areas under the curve AUCs calculated according to the trapezoidal rule. Post hoc two-sided t tests were used for single time point comparisons.

Intranasal insulin enhances postprandial energy expenditure. The rise in energy expenditure between baseline — a. and the postprandial state a. reflects the energy emitted mainly as heat during food metabolization diet-induced thermogenesis [DIT] right panel. Immediately after intranasal insulin administration, i.

placebo 4. placebo 1, ± 23 vs. In parallel with the slight postinsulin administration drop in plasma glucose, a small increase in serum insulin insulin vs. placebo Following liquid food intake, the postprandial increase in both insulin and C-peptide concentrations was reduced by intranasal insulin in comparison with placebo AUC, a.

Intranasal insulin lowers postprandial serum insulin levels. Concentrations of plasma glucose A , serum insulin B , serum C-peptide C , and serum free fatty acids D before and after acute intranasal administration nose symbol of intranasal insulin IU; solid lines and black bars and placebo dashed lines and white bars followed by the standardized ingestion of kcal of liquid food cup symbol.

Postprandial levels a. were also expressed as AUCs right panels. All values are presented as means ± SEM. We demonstrated in humans that acutely enhancing brain insulin signaling by intranasal administration of the hormone increases postprandial thermogenesis. The parallel treatment-induced reduction in postprandial serum insulin concentrations while plasma glucose levels were comparable between conditions indicates that following intranasal insulin administration to the brain, lower circulating levels of the hormone are sufficient to dispose of meal-related increases in plasma glucose.

In line with findings in animals 4 , 5 , 13 , our results support the notion that brain insulin signaling in humans is involved in the control of whole-body energy homeostasis.

In keeping with previous experiments 9 , 11 , intranasal administration of IU insulin induced a transient and mild increase in serum insulin concentrations accompanied by a slight drop in prefood intake plasma glucose that clearly remained within the euglycemic range.

Due to the relatively high dose administered here compared with that in previous studies 6 , 8 , a small ratio of the hormone may have entered the circulation via the nasal mucosa. However, the transient nature and limited size of these immediate effects argues against an involvement of systemic uptake of intranasal insulin in its impact on postprandial thermogenesis and glucose metabolism.

This conclusion is corroborated by the fact that immediate and postprandial effects were not statistically related.

The balanced regulation of nutrient intake and energy expenditure relies on the hypothalamus as a major integrator of nutritional and hormonal signals from the body periphery, including glucose and insulin 1. Direct injections of insulin into the preoptic area of the hypothalamus induce a dose-dependent increase in core body temperature due to stimulation of brown adipose tissue thermogenesis that is assumed to be mediated by inhibitory insulinergic action on warm-sensitive hypothalamic neurons 3.

In our experiments, intranasal administration of the hormone to the brain did not affect resting energy expenditure but evoked a distinct increase in postprandial thermogenesis.

Increased postprandial energy expenditure due to enhanced brain insulin signaling adds to the reduction in food intake previously observed after intranasal administration of the hormone 9 , suggesting that the catabolic impact of central nervous insulin 10 , 14 is mediated not only by anorexigenic but also by thermogenic effects of the hormone.

Still, further studies on this issue are needed and should include measurements of body temperature, brown adipose tissue activity, and relevant vital signs like heart rate and blood pressure to elucidate the effect of brain insulin signaling on energy expenditure in humans. A most remarkable finding of our study is the intranasal insulin—induced reduction in postprandial serum insulin concentrations while the food intake-induced rise in plasma glucose remained unaffected, suggesting that intranasal insulin improves postprandial insulin sensitivity.

A regulatory effect of central nervous insulin on hepatic glucose metabolism has been indicated by animal studies showing that a selective decrease in hypothalamic insulin receptors reduces hepatic insulin sensitivity and results in marked increases in hepatic glucose production in the presence of plasma insulin concentrations equaling those of control animals This pattern suggests that enhancing brain insulin signaling by intranasal administration of the hormone may act on glucose homeostasis in the body periphery by supporting hepatic insulin action.

Nevertheless, given that postprandial liver glucose production accounts for approximately one-fifth to one-half of fasting values 17 , improved insulin-dependent metabolization of ingested glucose may also have contributed to the intranasal insulin-induced decrease in postprandial serum insulin levels.

Such an effect could basically be supported by the observed decrease in prandial FFA levels due to intranasal insulin inasmuch as FFAs are known to impair insulin-stimulated muscle uptake of glucose However, FFA effects on peripheral insulin-stimulated glucose uptake slowly develop over some hours 19 , which, in conjunction with the lack of a significant correlation between the decreases in prandial FFA and postprandial insulin concentrations, makes this view unlikely.

Furthermore, a contribution of enhanced noninsulin-mediated glucose disposal, i. Although the present results suggest that insulin administration to the human brain enhances the efficiency of the glucoregulatory brain-liver axis in response to nutrient intake, our observations should be corroborated in future studies that rely on more refined measurements of insulin sensitivity, e.

It is also noteworthy that most recent animal data hint at divergent effects of hypothalamic insulinergic signaling on peripheral glucose homeostasis and energy expenditure depending on the involvement of agouti-related protein or proopiomelanocortin neuronal pathways In this regard, general enhancements in brain insulin signaling as performed in our study do not permit differentiations.

Taken together, our findings indicate that intranasal insulin acutely increases postprandial thermogenesis and improves the glucoregulatory response to food intake, suggesting that boosting brain insulin signaling in humans enhances the body's ability to cope with calorie consumption 20 , Against the background of studies indicating that obesity and peripheral insulin resistance are associated with reduced central nervous insulin sensitivity 22 , — 24 , enhancing brain insulin signaling may emerge as a useful approach in the therapeutic management of disorders hallmarked by disturbed glucose homeostasis The costs of publication of this article were defrayed in part by the payment of page charges.

Section solely to indicate this fact. The funding sources had no input in the design and conduct of this study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

Aero Pump, Hochheim, Germany, generously provided us with precision nasal air pumps. DIT measured at 24°C was unaltered Table 2. Monthly acclimation did not alter EMG recordings, and subjects did not report changes in cold perception at 19°C during monthly calorimeter testing Supplementary Fig.

Neither total caloric nor macronutrient content of intake changed during acclimation Table 3. Biweekly hunger and satiety scores did not change significantly Table 3 ; however, volunteers reported an increase in desire to eat and reduction in satiety during ad libitum meal test after cold acclimation, which reversed during the warm months Supplementary Fig.

Body composition was unaltered across the study period Table 3. To elucidate potential endocrine mediators of BAT acclimation, we profiled pituitary-thyroid-adrenal axes Table 4. Cold acclimation increased free triiodothyronine T3 AUC measured at 24°C but not at 19°C.

No significant changes were observed in thyrotropin thyroid-stimulating hormone [TSH] or the pituitary-adrenal axis. Total glucose and insulin AUCs did not change during acclimation Table 4. In contrast, postprandial insulin excursion measured at 19°C reached a nadir after cold acclimation, without significant changes to glucose excursion Fig.

Indices of insulin sensitivity and resistance showed significant reciprocal changes during cold and warm acclimation, consistent with an improvement of postprandial whole-body insulin sensitivity after cold acclimation Fig. These changes were absent during measurements at 24°C Fig.

Metabolic consequences of BAT acclimation at 19°C. A and B : Comparison of postprandial glucose and insulin excursions after a mixed meal at h before and after cold acclimation, respectively, measured at 19°C.

Glucose excursions were unchanged but insulin levels decreased, with a significant reduction in AUC, after mild cold acclimation month 2. Accordingly, adipocyte insulin resistance IR was the lowest C and Matsuda index an indicator of insulin sensitivity was the highest D after cold acclimation month 2.

These changes in glucose metabolism were accompanied by an increase in circulating adiponectin E and a decrease in circulating leptin F. Cold acclimation—induced changes months 1 and 2 in circulating adiponectin G and leptin levels H correlated negatively with changes in BAT activity.

Adiponectin and leptin mRNA displayed concordant changes in subcutaneous adipose tissue biopsies with circulating levels, and changes in GLUT4 tracked those of adiponectin I. Metabolic consequences of BAT acclimatization at 24°C.

A and B : Comparison of postprandial glucose and insulin excursions after a mixed meal at h before and after cold acclimatization, respectively, measured at 24°C.

Unlike measurements at 19°C Fig. Accordingly, adipocyte insulin resistance IR C and Matsuda index an indicator of insulin sensitivity D were unchanged.

Circulating adiponectin increased E , while leptin decreased F , identical to measurements observed at 19°C Fig. Cold acclimatization—induced changes months 1 and 2 in circulating adiponectin G and leptin levels H correlated negatively with changes in BAT activity.

In contrast to that observed in adipose tissue Fig. Given our recent demonstration of BAT as an endocrine organ in humans 19 , 32 , 35 , we probed adipokine changes during acclimation. Changes in circulating adiponectin and leptin correlated negatively with changes in BAT activity after cold acclimation Fig.

FGF21 AUC rose after cold acclimation, although overall trend did not reach significance Table 4. For exploration of sources of adipokine and origins of metabolic changes, fat and muscle biopsies were obtained from four volunteers at the end of each month.

Adiponectin and GLUT4 expression in adipose tissue Fig. Expression of CIDEA , a BAT gene governing lipid mobilization 36 , increased after cold acclimation but decreased during rewarming Fig. BAT and beige fat gene changes in adipose tissue biopsies across 4-month acclimatization. A : Changes in general BAT gene expression general BAT genes are defined as genes ascribed to general BAT function and do not indicate their developmental origin.

B : Changes in classic BAT gene expression. Classic BAT genes are defined as those expressed in interscapular BAT in animals or human infants C : Changes in beige fat gene expression. Beige fat genes are defined as those expressed in inducible brown adipocytes, also known as brite or beige adipocytes, found within WAT depots.

No significant changes were observed in classic BAT or beige fat genes across temperature acclimation. The major finding of our study is the demonstration of BAT acclimation and its metabolic consequences by minimal manipulation of overnight temperature exposure while allowing usual daily activities.

Human BAT is inducible and suppressible by controlled mild cold and warm exposure, respectively, independent of seasonal fluctuations. BAT acclimation is accompanied by boosting of DIT and postprandial insulin sensitivity.

Mechanistically, this is associated with reciprocal changes of circulating adiponectin and leptin, mirrored by corresponding transcriptosomal changes in adipose tissue ex vivo. Consistent with previous reports 25 , 26 , we confirmed BAT recruitability by cold exposure but did not observe significant CIT response augmentation; the latter could be a type 2 error.

Despite tentalizing associative data linking BAT abundance with favorable energy metabolism in humans, it remains unclear, to date, whether BAT recruitment is accompanied by metabolic benefits.

We specifically sought to determine the significance of BAT recruitment and revealed an association of BAT acclimation with enhancement of postprandial energy metabolism and insulin sensitization. Within the allowance and feasibility of human research, we explored underlying mechanisms through blood and tissue analyses.

First, within the pituitary-thyroid-adrenal axis, we observed an increase in T3-to-T4 ratio, which indicates enhanced T3 synthesis.

Given the enrichment of BAT with type 2 deiodinase 37 and our previous report showing severe insulin resistance amelioration by thyroid hormone-mediated BAT activation 38 , we hypothesize heightened T3 synthesis within BAT to be one plausible mechanism underlying acclimated-BAT associated metabolic changes.

Such a pattern of increased thyroid hormone turnover in the absence of TSH changes is reminiscent of cold adaptation observed among Arctic residents Second, our adipokine profiling uncovered an intriguing relation between BAT, adiponectin, and leptin.

Cold acclimation augmented circulating adiponectin but decreased leptin. It is tempting to speculate that cold-induced adiponectin, a potent insulin sensitizer, contributes to glucose metabolism improvement and leptin reduction, with the latter as a result of improved tissue sensitivity.

Concordant gene changes in adipose adiponectin and leptin, absent in muscle, argue adipose to be the primary effector. Surprisingly, circulating adiponectin related negatively with BAT activity, suggesting that PET-detectable BAT was not the source of cold-induced adiponectin.

As BAT exhibits insulin-independent glucose uptake capacity 40 , lesser BAT expansion could have triggered alternative glucose utilizing pathways in WAT during cold acclimation, evident by observed WAT GLUT4 upregulation.

Interestingly, such changes in circulating adiponectin and leptin were not limited to the cold-exposed condition Fig. The corollary is that acclimated BAT could be serving beneficial metabolic functions not related to temperature regulation per se.

Third, newly identified cytokines, such as FGF21, may mediate temperature-acclimated tissue cross-talk. Recent identification of a FGFadiponectin feed-forward axis 41 led us to wonder whether FGF21 augmentation after cold acclimation could have brought forth the adiponectin rise.

When BAT was muted at the end of warm acclimation and adiponectin dwindled, FGF21 did not fall, suggesting that non-BAT FGF-secreting tissues might have compensated in states of relative BAT deficiency.

Fourth, although we did not observe an increase in beige fat gene expression, possibly due to the small sample size, we speculate fat browning to be a possibility. This is corroborated by finding an increased expression of the BAT gene CIDEA in adipose tissue after cold acclimation. Compared with WAT, BAT has relatively less lipid, as it is filled with abundant mitochondria and blood vessels.

This is exemplified by water-fat separated magnetic resonance imaging revealing a lower fat fraction in activated BAT both in humans 42 and in rodents This is also supported by previous studies demonstrating cell-autonomous 44 and endocrine-mediated 19 cold-induced WAT browning in humans.

Further studies are required to ascertain whether WAT browning contributes to cold-acclimated BAT-induced metabolic changes.

Most importantly, all these changes occurred in the absence of measureable EE, caloric intake, or body compositional alterations, suggesting such responses to be primary cold-induced metabolic sequelae rather than compensatory physiologic adaptations.

Nonetheless, because the desire to eat heightened after cold acclimation, we cannot exclude the possibility that appetite stimulation could diminish metabolic benefits of BAT recruitment if it increases caloric intake in longer-term studies. The inducibility, suppressibility, and plasticity of human BAT entail implications beyond thermoregulatory physiology.

The translation of recently discovered BAT activators in the laboratory to pharmacologic BAT stimulants available for clinical use is not a trivial process Our study substantiates, in contrast, a simple BAT-modulating strategy: a mild reduction in environmental temperature is capable of recruiting BAT and yielding associated metabolic benefits; conversely, even a small elevation in ambient temperature could impair BAT and dampen previously attained metabolic benefits.

Such reversible metabolic switching, occurring within a temperature range achievable in climate-controlled buildings, therefore carries therapeutic implications of BAT acclimation both on an individual and a public health level.

Bedroom temperature has gradually increased from 19°C to The blunting of BAT function due to widespread use of indoor climate control could be a neglected contribution to the obesity epidemic. Moderate downward adjustment of indoor temperature could represent a simple and plausible strategy in dampening the escalation of obesity on a population level.

Our volunteers reported satisfactory sleep during acclimation, although more formal assessment of sleep quality is required in future studies.

Our findings should be viewed as a proof of concept illustrating human BAT plasticity. We acknowledge the small sample size to be a limitation of our study. Unfortunately, the conduct of long-term acclimation study necessitated substantial resources and regrettably prohibited a large sample size.

The unveiled positive relation between acclimated BAT and glucose homeostasis is clinically relevant. Glucose intolerance is an independent risk factor of cardiovascular mortality, and postprandial hyperglycemia is its earliest manifestation We emphasize that a causal linkage could not be definitely ascertained between BAT recruitment and postprandial insulin sensitivity improvement; however, our study provides compelling circumstantial evidence supporting a potential therapeutic role of BAT in impaired glucose metabolism and calls for the investigation of similar temperature acclimation in individuals with impaired glycemia.

Our observation of BAT recruitment accompanied by insulin sensitization in the absence of significant weight loss echoes animal findings showing glucose homeostasis improvement after fat browning to be greater than expected from adiposity reduction alone 49 , In summary, temperature acclimation modulates BAT abundance and activity, subsequently impacting energy and substrate metabolism in humans.

BAT exhibits thermal plasticity intimately related to glucose homeostasis. Harnessing BAT by simple adjustment of ambient temperature could be a new strategy in the combat against obesity, diabetes, and related disorders.

Clinical trial reg. NCT, clinicaltrials. The authors thank Dr. Peter Herscovitch and Dr. This study was supported by the Intramural Research Program ZDK of NIDDK and the NIH Clinical Center. was supported by an Australian National Health and Medical Research Council Early Career Fellowship, the Diabetes Australia Fellowship and Bushell Travelling Fellowship, and the School of Medicine, University of Queensland.

The funders had no role in the design or conduct of the study; collection, management, analysis, or interpretation of data; or preparation, review, or approval of the manuscript.

Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. participated in the development of the study concept and design, research, acquisition of data, and analysis and discussion of results; wrote the manuscript; participated in critical revision; and approved the final version of the manuscript.

participated in the development of the study concept and design, research, acquisition of data and analysis and discussion of results; participated in critical revision; and approved the final version of the manuscript.

Barlow, C. Targeted expression of Cre recombinase to adipose tissue of transgenic mice directs adipose-specific excision of lox P-flanked gene segments.

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Hotta, K. Circulating concentrations of the adipocyte protein, adiponectin, are decreased in parallel with reduced insulin sensitivity during the progression to type-2 diabetes in rhesus monkeys. Diabetes 50 , — Kawamoto, S. A novel reporter mouse that express enhanced green fluorescent protein upon Cre-mediated recombination.

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Download references. We thank Y. Matsuzawa and K. Sugihara for their encouragement, and K. Nishida, K. Oiki and S. Mizuno for technical assistance.

This work was supported in part by grants from the Suzuken Memorial Foundation, The Nakajima Foundation, Kanae Foundation for Life and Socio-Medical Science, The Tokyo Biochemical Research Foundation, Takeda Medical Research Foundation, Uehara Memorial Foundation, Takeda Science Foundation, Novartis Foundation Japan for the Promotion of Science, The Cell Science Research Foundation, The Mochida Memorial Foundation for Medical and Pharmaceutical Research, a Grant-in-Aid from the Japan Medical Association, The Naito Foundation, a grant from the Japan Heart Foundation Research, Kato Memorial Bioscience Foundation, Japan Research Foundation for Clinical Pharmacology, a grant from the Ministry of Health, Labor and Welfare, Japan, and Grants-in-Aid from COE Research and Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

Department of Social and Environmental Medicine, Graduate School of Frontier Bioscience, Osaka University, Yamadaoka, Suita, , Osaka. Department of Medicine and Pathophysiology, Graduate School of Frontier Bioscience, Osaka University, Yamadaoka, Suita, , Osaka.

Macor, C. De Palo, S. Favro, R. Vettor, G. Federspil, C.

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What Is Insulin Resistance?

Thermogenesis and insulin sensitivity -

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Top Abstract Version history. Published in Volume 89, Issue 3 on March 1, J Clin Invest. Published March 1, - Version history. Abstract The putative blunted thermogenesis in obesity may be related to insulin resistance, but insulin sensitivity and obesity are potentially confounding factors.

View PDF of the complete article page page Version 1 March 1, : No description. Moreover, GRP75 knockdown impaired thermogenesis and glucose utilization in brown adipocytes, the adipocytes with abundant mitochondria that regulate whole-body energy homeostasis.

Taken together, our findings suggest that MAMs formation is essential for promoting mitochondrial function and maintaining a proper redox status to enable the differentiation of preadipocytes and normal functioning such as insulin signaling and thermogenesis in mature adipocytes.

Increasing evidence has supported a causative relationship between mitochondrial dysfunction and the pathogenesis of type 2 diabetes T2D and insulin insensitivity Petersen et al. It has been reported that the tissues of mice and human subjects with insulin insensitivity or T2D display lower expression levels of respiratory enzyme complexes or proteins essential for mitochondrial biogenesis, impaired respiratory function or defects in the β oxidation of fatty acids.

Decline in mitochondrial bioenergetic function is commonly observed in insulin-responsive tissues muscle and adipose tissues of diabetic mice or T2D patients. Moreover, more profound decline in mitochondrial function would lead to more severe hyperglycemia and insulin insensitivity of diabetic patients and mouse models Lim et al.

These observations strongly support the concept that mitochondrial dysfunction is one of the major etiological factors for T2D and insulin resistance. In addition to mitochondrial defects, abnormality of endoplasmic reticulum ER is also associated with T2D.

Chronic ER stress and dysregulation of unfolded protein response UPR are involved in the mechanisms underlying obesity-induced insulin insensitivity.

However, alleviation of ER stress by treatment of diabetic mice with 4-phenyl butyric acid 4-PBA and taurine-conjugated ursodeoxycholic acid TUDCA was found to improve the metabolic abnormalities in these mice Ozcan et al.

Mitochondria and ER are two intracellular organelles that play a key role in the maintenance of cellular homeostasis. Alterations in the crosstalk between mitochondria and ER could result in the development of T2D.

Mitochondria-associated ER membranes MAMs are the contact sites between the mitochondrial outer membrane and ER Patergnani et al. The MAMs refer to a bridge region of two membranes where the distance between the two organelles is less than 25 nm Csordas et al.

The physical interactions between both organelles depend on complementary membrane proteins, which tether the two organelles together at specific sites. It was further demonstrated that the MAMs architecture involves a large number of proteins with various functions Yang et al.

In the present study, we found that the formation of MAMs is increased during adipogenic differentiation of 3T3-L1 cells. The disruption of MAMs by knock-down of GRP75, a protein involved in MAMs formation, led to the impairment of differentiation and mitochondrial dysfunction although there was a compensatory upregulation of mitochondrial biogenesis.

Ultimately, increase of the ROS level due to imbalance of the antioxidant system impaired the insulin sensitivity and thermogenic function in mature white and brown adipocytes with GRP75 deficiency, respectively. In all experiments, 3T3-L1 and brown preadipocytes were used for differentiation to mature adipocytes within 5 passages.

All the experiments were conducted by using the adipocytes 7 days after differentiation. All the experiments were conducted by using the brown adipocytes 7 days after differentiation.

The lentiviruses containing two different small hairpin RNA shRNA constructs of the GRP5 gene GRP75 KD 1 and 2 and random sequences CTL KD were obtained from the RNAi Core Facility at Academia Sinica, Taipei, Taiwan. The targeting sequences of CTL KD and GRP75 KD in the pLKO. Briefly, 1 mg total protein lysate of 3T3-L1 cells was incubated with specific primary antibodies α-IP3R1 or α-GRP75 at 4°C overnight, which was followed by incubating the mixture with 20 μl of immunocapture beads at 4°C for 4 h.

After washing with the TBST buffer 50 mM Tris-HCl, mM NaCl, and 0. Total cellular RNA was extracted with chloroform after addition of the TRIzol Reagent Invitrogen , precipitated with isopropanol and then dissolved in DEPC-H 2 O. An aliquot of 5 µg RNA was reverse-transcribed into cDNA using a Ready-to-Go RT-PCR kit GE Healthcare Life Sciences at 42°C for at least 16 h.

The mRNA expression levels of the target genes were normalized against the attachment region binding protein ARBP.

The sequences of the primer pairs are listed in Table 2. Cells were incubated with the lysis buffer containing 50 mM HEPES pH 7. After blocking, the membrane was hybridized with the indicated primary antibodies and the corresponding HRP-conjugated secondary antibody.

Finally, the protein bands were visualized by an ECL chemiluminescence reagent Perkin-Elmer Life Sciences and the band intensities were determined using a Luminescence Imaging System Model LAS GE Healthcare Life Sciences, Chicago, IL.

All the data were normalized against an internal control, actin or β tubulin. The primary antibodies against IP3R1, p-AKT ser , total AKT, MCU and β tubulin were obtained from Cell Signaling Technology Danvers, MA , the antibody against GRP75 was purchased from Proteintech Rosemont, IL , antibodies against VDAC1 and actin were obtained from Merck Millipore Billerica, MA.

After adipogenic differentiation, the mature 3T3L1 adipocytes were incubated with a serum-free medium for 4 h and then treated with insulin-stimulated group or without basal group nM insulin for 30 min to activate insulin signaling pathway.

The adipocytes were incubated with 5 μM MitoSOX Red or 80 μM DCFH 2 -DA in the medium at 37°C in the dark for 30 min. After washing with PBS, the relative fluorescence intensity of MitoSOX or DCF in 10, cells per sample was determined on a flow cytometer Model EPICS XL-MCL, Beckman-Coulter, Miami, FL.

Mature adipocytes were incubated with 1 μM Fluo-4 AM, at 37°C in the dark for 30 min. After washing with PBS, the levels of calcium-bound Fluo-4 in cytosol of adipocytes were determined by a flow cytometer using the excitation wavelength at nm and emission wavelength at nm.

Glucose uptake was measured by using 2-[N- 7-nitrobenzoxa-1,3-diazolyl amino]deoxy- d -glucose 2-NBDG , a fluorescent glucose analog, according to the previous protocol Yamada et al.

Adipocytes were grown in a serum-free medium for 4 h and the medium was then replaced by a KRH buffer KRP buffer containing 20 mM HEPES, pH 7. The adipocytes were stimulated with insulin-stimulated group or without basal group addition of nM insulin. After incubation for 30 min, a suitable volume of 50 μM 2-NBDG in KRH buffer was directly added to allow the cells to uptake 2-NBDG for 20 min.

Insulin was placed totally for 50 min. After washing with PBS, the 2-NBDG uptake was determined on a flow cytometer using the excitation wavelength at nm and emission wavelength at nm. Statistical analyses were performed using the Microsoft Excel statistical package and the data are presented as means ± SEM of the results obtained from 3 or more independent experiments.

To examine the change of MAM formation during differentiation of 3T3-L1, we collected the RNA samples at different time points day 0, 3, 7 after adipogenic induction and measured the expression levels of genes involved in the MAMs structure.

The results showed that the channel protein IP3R1 in the ER, and the channel proteins in mitochondrial outer and inner membranes, VDAC1 and MCU, respectively, were all upregulated during adipogenic differentiation Figure 1A.

However, GRP75, the linker between IP3R1 and VDAC1 to connect ER and mitochondria, was not changed during differentiation Figure 1A. In addition, we extracted total cellular proteins before and after adipogenic differentiation of 3T3-L1 preadipocytes. Similar to the results obtained from the expression study of mRNA, the protein levels of IP3R1, VDAC1 and MCU were all upregulated after adipogenic differentiation but no change in the GRP75 protein Figure 1B.

FIGURE 1. Increased expression levels of MAMs-related genes after adipogenic differentiation. A The mRNA levels of genes involved in the formation of MAMs structure on day 0, 3, 7 after adipogenic differentiation of 3T3-L1 preadipocytes.

B The protein levels of genes involved in the formation of MAMs structure before Day 0 and 7 days after adipogenic differentiation of 3T3-L1 preadipocytes. Data are presented as means ± SEM. To check whether the formation of MAM structure is increased, we measured the interaction between IP3R1, GRP75 and VDAC1 using co-immunoprecipitation assay.

We used anti-IP3R1 antibody to precipitate IP3R1 and its interacting proteins or protein complexes in the samples extracted before day 0 and 7 days after adipogenic differentiation of 3T3-L1 preadipocytes. The results showed that after immunoprecipitation of IP3R1 with a limited amount of the primary antibody, an equal amount of IP3R1 was pulled down in the samples from day 0 and day 7 of differentiation although there was a high level of IP3R1 in the total lysate at day 7 Figure 2A.

We then used these IP3R1-immunoprecipitated samples to detect GRP75 and VDAC1 via immunoblotting Figure 2B. We found that more GRP75 and VDAC1 proteins could be detected when the same amount of IP3R1 had been pulled down on day 7 compared to day 0 after differentiation Figure 2B , left panel and Supplementary Figure S1.

There are 2-fold or 4-fold increases in the interaction between GRP75 and IP3R1 or VDAC1 and IP3R1, respectively after 7 days of differentiation Figure 2B , right panel. On the other hand, to further confirm the increase of MAMs formation during differentiation, we did the reciprocal co-immunoprecipitation.

Similarly, after precipitating the same amount of GRP75 by its primary antibody Figure 2C , 1. Taken together, these findings suggest that MAMs formation i. FIGURE 2. Increase of MAMs formation after adipogenic differentiation.

A,B Protein lysates from 3T3-L1 preadipocytes Day 0 and adipocytes Day 7 after differentiation were pulled down by an anti-IP3R1 antibody A and followed by detection of GRP75 and VDAC1 proteins using Western blot analysis B, right panel.

The MAMs formation was calculated by the ratio of interaction between IP3R1 and GRP75 and between IP3R1 and VDAC1, respectively B, left panel.

C,D Protein lysates from 3T3-L1 preadipocytes Day 0 and adipocytes Day 7 after differentiation were pulled down by an anti-GRP75 antibody C and followed by detection of IP3R1 and VDAC1 using Western blot analysis D, right panel.

The MAMs formation was calculated by the ratio of interaction between GRP75 and IP3R1 and between GRP75 and VDAC1, respectively D, left panel. To determine the importance of MAMs formation in the differentiation and function of adipocytes, we disrupted the MAMs structure by knocking down the proteins involved in MAMs formation.

Because IP3R1 and VDAC1 may have other exclusive roles in the function of ER and mitochondria, respectively, we decided to target GRP75, which is a linker between ER and mitochondria and its level was not changed during differentiation Figure 1.

We designed two different sequences of shRNA to knock down GRP75 in 3T3-L1 preadipocytes. Most importantly, the knockdown of GRP75 was sustained for 7 days after adipogenic differentiation. To determine the adipogenic differentiation capacity of 3T3-L1 with GRP75 KD, the adipocyte markers PPARγ2, aP2 known as FABP4 and adiponectin were examined.

The results revealed that the expression levels of these 3 genes were decreased after differentiation of 3T3-L1 preadipocytes with GRP75 KD Figure 3C. In addition, we stained lipid droplets of adipocytes by Oil red O.

In consistency with gene markers Figure 3C , GRP75 deficiency led to the decreased formation of lipid droplets after 3T3-L1 differentiation Figure 3D. These findings indicate that the disruption of MAMs structure by knock-down of GRP75 could impair the adipogenic differentiation of 3T3-L1 preadipocytes.

FIGURE 3. Impairment of adipogenic differentiation of 3T3-L1 preadipocytes with GRP75 knockdown. A The protein levels of GRP75 were determined in 3T3-L1 preadipocytes after delivering shRNA with scramble sequence CTL or two different sequences targeting to GRP75 KD 1 and KD 2.

The quantification of protein bands was shown in the left panel. B,C The 3T3-L1 preadipocytes with CTL KD, GRP75 KD 1 and GRP75 KD 2 were induced to undergo adipogenic differentiation for 7 days. D The 3T3-L1 preadipocytes with CTL KD, GRP75 KD 1 and GRP75 KD 2 were induced to undergo adipogenic differentiation for 7 days and were then stained by Oil red O.

Next, we examined whether disruption of MAMs structure affects the mitochondrial function during adipogenic differentiation.

Surprisingly, adipocytes with GRP75 KD displayed upregulation of genes involved in mitochondrial biogenesis, such as PGC1α Figure 4A. However, the increase of mitochondrial biogenesis did not lead to the increase of mitochondrial function in adipocytes.

The adipocytes with GPR75 KD expressed less MnSOD Figure 4C , which is a first-line antioxidant enzyme, leading to accumulation of intracellular reactive oxygen species ROS such as superoxide anions Figure 4D and hydrogen peroxide Figure 4E. Book Chapter. Macor C.

Institute of Semeiotica Medica, Patologia Medica III, University of Padua, Italy. De Palo C. De Palo. Favro S. Vettor R. Federspil G. Scandellari C. Publication history 0 4. Cite Icon Cite. toolbar search search input Search input auto suggest.

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