Cold acclimation and pioglitazone combined increase thermogenic capacity of brown and white adipose tissues but this does not translate into higher energy expenditure in mice.

Cold acclimation and pharmacological peroxisome proliferator-activated receptor γ (PPARγ) activation have each earlier been shown to recruit brown adipose tissue (BAT) and beige adipocytes thermogenic machinery, enhancing uncoupling protein 1 (UCP1)-mediated thermogenic capacity. We here investigated whether cold acclimation and PPARγ agonism combined have additive effects in inducing brown and beige adipocytes UCP1 content and whether this translates into a higher thermogenic capacity and energy expenditure. C57BL/6J mice treated or not with pioglitazone (30 mg/kg/day) were maintained at 21°C or exposed to cold (7°C) for 15 days and evaluated for thermogenic capacity, energy expenditure and interscapular BAT (iBAT) and inguinal white adipose tissue (iWAT) mass, morphology, UCP1 content and gene expression, glucose uptake and oxygen consumption. Cold acclimation and PPARγ agonism combined synergistically increased iBAT and iWAT total UCP1 content and mRNA levels of the thermogenesis-related proteins PGC1a, CIDEA, FABP4, GYK, PPARa, LPL, GLUTs (GLUT1 in iBAT and GLUT4 in iWAT), and ATG when compared to cold and pioglitazone individually. This translated into a stronger increase in body temperature in response to the ß3-adrenergic agonist CL316,243 and iBAT and iWAT respiration induced by succinate and pyruvate in comparison to that seen in either cold-acclimated or pioglitazone-treated mice. However, basal energy expenditure, BAT glucose uptake and glucose tolerance were not increased above that seen in cold-acclimated untreated mice. In conclusion, cold acclimation and PPARγ agonism combined induced a robust increase in brown and beige adipocytes UCP1 content and thermogenic capacity, much higher than each treatment individually. However, our findings enforce the concept that increases in total UCP1 do not innately lead to higher energy expenditure.NEW & NOTEWORTHY Cold acclimation and PPARγ agonism combined markedly increase brown and white adipose tissue total UCP1 content and mRNA levels of thermogenesis-related proteins. Higher UCP1 protein levels did not result in higher energy expenditure. The high thermogenic capacity induced by PPARγ agonism in cold-exposed animals markedly increases animals' body temperature in response to the ß3-adrenergic agonist CL316,243.

Adipocyte-specific mTORC2 deficiency impairs BAT and iWAT thermogenic capacity without affecting glucose uptake and energy expenditure in cold-acclimated mice.

Deletion of mechanistic target of rapamycin complex 2 (mTORC2) essential component rapamycin insensitive companion of mTOR (Rictor) by a Cre recombinase under control of the broad, nonadipocyte-specific aP2/FABP4 promoter impairs thermoregulation and brown adipose tissue (BAT) glucose uptake on acute cold exposure. We investigated herein whether adipocyte-specific mTORC2 deficiency affects BAT and inguinal white adipose tissue (iWAT) signaling, metabolism, and thermogenesis in cold-acclimated mice. For this, 8-wk-old male mice bearing Rictor deletion and therefore mTORC2 deficiency in adipocytes (adiponectin-Cre) and littermates controls were either kept at thermoneutrality (30 ± 1°C) or cold-acclimated (10 ± 1°C) for 14 days and evaluated for BAT and iWAT signaling, metabolism, and thermogenesis. Cold acclimation inhibited mTORC2 in BAT and iWAT, but its residual activity is still required for the cold-induced increases in BAT adipocyte number, total UCP-1 content and mRNA levels of proliferation markers Ki67 and cyclin 1 D, and de novo lipogenesis enzymes ATP-citrate lyase and acetyl-CoA carboxylase. In iWAT, mTORC2 residual activity is partially required for the cold-induced increases in multilocular adipocytes, mitochondrial mass, and uncoupling protein 1 (UCP-1) content. Conversely, BAT mTORC1 activity and BAT and iWAT glucose uptake were upregulated by cold independently of mTORC2. Noteworthy, the impairment in BAT and iWAT total UCP-1 content and thermogenic capacity induced by adipocyte mTORC2 deficiency had no major impact on whole body energy expenditure in cold-acclimated mice due to a compensatory activation of muscle shivering. In conclusion, adipocyte mTORC2 deficiency impairs, through different mechanisms, BAT and iWAT total UCP-1 content and thermogenic capacity in cold-acclimated mice, without affecting glucose uptake and whole body energy expenditure.NEW & NOTEWORTHY BAT and iWAT mTORC2 is inhibited by cold acclimation, but its residual activity is required for cold-induced increases in total UCP-1 content and thermogenic capacity, but not glucose uptake and mTORC1 activity. The impaired BAT and iWAT total UCP-1 content and thermogenic capacity induced by adipocyte mTORC2 deficiency are compensated by activation of muscle shivering in cold-acclimated mice.

Fish Oil Protects Wild Type and Uncoupling Protein 1-Deficient Mice from Obesity and Glucose Intolerance by Increasing Energy Expenditure.

SCOPE: The mechanisms and involvement of uncoupling protein 1 (UCP1) in the protection from obesity and insulin resistance induced by intake of a high-fat diet rich in omega-3 (n-3) fatty acids are investigated. METHODS AND RESULTS: C57BL/6J mice are fed either a low-fat (control group) or one of two isocaloric high-fat diets containing either lard (HFD) or fish oil (HFN3) as fat source and evaluated for body weight, adiposity, energy expenditure, glucose homeostasis, and inguinal white and interscapular brown adipose tissue (iWAT and iBAT, respectively) gene expression, lipidome, and mitochondrial bioenergetics. HFN3 intake protected from obesity, glucose and insulin intolerances, and hyperinsulinemia. This is associated with increased energy expenditure, iWAT UCP1 expression, and incorporation of n-3 eicosapentaenoic and docosahexaenoic fatty acids in iWAT and iBAT triacylglycerol. Importantly, HFN3 is equally effective in reducing body weight gain, adiposity, and glucose intolerance and increasing energy expenditure in wild-type and UCP1-deficient mice without recruiting other thermogenic processes in iWAT and iBAT, such as mitochondrial uncoupling and SERCA-mediated calcium and creatine-driven substrate cyclings. CONCLUSION: Intake of a high-fat diet rich in omega-3 fatty acids protects both wild-type and UCP1-deficient mice from obesity and insulin resistance by increasing energy expenditure through unknown mechanisms.

Critical review of beige adipocyte thermogenic activation and contribution to whole-body energy expenditure.

Beige (or brite, "brown in white") adipocytes are uncoupling protein 1 (UCP1)-positive cells residing in white adipose depots that, depending on the conditions, behave either as classic white adipocytes, storing energy as lipids, or as brown adipocytes, dissipating energy from oxidative metabolism as heat through non-shivering thermogenesis. Because of their thermogenic potential and, therefore, possible usage to treat metabolic diseases such as obesity and type 2 diabetes, beige cells have attracted the attention of many scientists worldwide aiming to develop strategies to safely recruit and activate their thermogenic activity. Indeed, in recent years, a large variety of conditions, molecules (including nutrients) and signaling pathways were reported to promote the recruitment of beige adipocytes. Despite of those advances, the true contribution of beige adipocyte thermogenesis to whole-body energy expenditure is still not completely defined. Herein, we discuss some important aspects that should be considered when studying beige adipocyte biology and the contribution to energy balance and whole-body metabolism.