Content of stress granules reveals a sex difference at the early phase of cold exposure in mice.

Adaptive thermogenesis is a vital physiological process for small endotherms. Female animals usually are more sensitive to cold temperature due to anatomical differences. Whether there is a sex difference at a molecular level is unclear. Stress granules (SGs) are dynamic organelles in which untranslated mRNAs reside during cellular stress. We hypothesize that the prompt response of SGs to cold stress can reveal the molecular difference between sexes. By analyzing the content in SGs of brown adipose tissue (BAT) at the early phase of cold stress for both sexes, we found more diverse mRNAs docked in the SGs in male mice and these mRNAs representing an extensive cellular reprogramming including apoptosis process and cold-induced thermogenesis. In female mice, the mRNAs in SGs dominantly were comprised of genes regulating ribonucleoprotein complex biogenesis. Conversely, the proteome in SGs was commonly characterized as structure molecules and RNA processing for both sexes. A spectrum of eukaryotic initiation factors (eIFs) was detected in the SGs of both female and male BAT, while those remained unchanged upon cold stress in male mice, various eIF3 and eIF4G isoforms were found reduced in female mice. Taken together, the unique features in SGs of male BAT reflected a prompt uncoupling protein-1 (UCP1) induction which was absent in female, and female, by contrast, were prepared for long-term transcriptional and translational adaptations.NEW & NOTEWORTHY The proteome analysis reveals that stress granules are the predominant form of cytosolic messenger ribonucleoproteins of brown adipose tissue (BAT) at the early phase of cold exposure in mice for both sexes. The transcriptome of stress granules of BAT unveils a sex difference of molecular response in early phase of cold exposure in mice, and such difference prepares for a prompt response to cold stress in male mice while for long-term adaptation in female mice.

Glycogen synthesis is required for adaptive thermogenesis in beige adipose tissue and affects diet-induced obesity.

Glycogen is a form of energy storage for glucose in different tissues such as liver and skeletal muscle. It remains incompletely understood how glycogen impacts on adipose tissue functionality. Cold exposure elevated the expression of Gys1 that encodes glycogen synthase 1 in brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT). The in vivo function of Gys1 was analyzed using a mouse model in which Gys1 was deleted specifically in adipose tissues. Under normal chow conditions, Gys1 deletion caused little changes to body weight and glucose metabolism. Deletion of Gys1 abrogated upregulation of UCP1 and other thermogenesis-related genes in iWAT upon prolonged cold exposure or treatment with ß3-adrenergic receptor agonist CL-316,243. Stimulation of UCP1 by CL-316,243 in adipose-derived stromal cells (stromal vascular fractions, SVFs) was also reduced by Gys1 deletion. Both the basal glycogen content and CL-316,243-stimulated glycogen accumulation in adipose tissues were reduced by Gys1 deletion. High-fat diet-induced obesity and insulin resistance were aggravated in Gys1-deleted mice. The loss of body weight upon CL-316,243 treatment was also abrogated by the loss of Gys1. In conclusion, our results underscore the pivotal role of glycogen synthesis in adaptive thermogenesis in beige adipose tissue and its impact on diet-induced obesity in mice.NEW & NOTEWORTHY Glycogen is one of major types of fuel reserve in the body and its classical function is to maintain blood glucose level. This study uncovers that glycogen synthesis is required for beige fat tissue to generate heat upon cold exposure. Such a function of glycogen is linked to development of high-fat diet-induced obesity, thus extending our understanding about the physiological functions of glycogen.

Essential role of systemic iron mobilization and redistribution for adaptive thermogenesis through HIF2-α/hepcidin axis.

Iron is an essential biometal, but is toxic if it exists in excess. Therefore, iron content is tightly regulated at cellular and systemic levels to meet metabolic demands but to avoid toxicity. We have recently reported that adaptive thermogenesis, a critical metabolic pathway to maintain whole-body energy homeostasis, is an iron-demanding process for rapid biogenesis of mitochondria. However, little information is available on iron mobilization from storage sites to thermogenic fat. This study aimed to determine the iron-regulatory network that underlies beige adipogenesis. We hypothesized that thermogenic stimulus initiates the signaling interplay between adipocyte iron demands and systemic iron liberation, resulting in iron redistribution into beige fat. To test this hypothesis, we induced reversible activation of beige adipogenesis in C57BL/6 mice by administering a ß3-adrenoreceptor agonist CL 316,243 (CL). Our results revealed that CL stimulation induced the iron-regulatory protein-mediated iron import into adipocytes, suppressed hepcidin transcription, and mobilized iron from the spleen. Mechanistically, CL stimulation induced an acute activation of hypoxia-inducible factor 2-α (HIF2-α), erythropoietin production, and splenic erythroid maturation, leading to hepcidin suppression. Disruption of systemic iron homeostasis by pharmacological HIF2-α inhibitor PT2385 or exogenous administration of hepcidin-25 significantly impaired beige fat development. Our findings suggest that securing iron availability via coordinated interplay between renal hypoxia and hepcidin down-regulation is a fundamental mechanism to activate adaptive thermogenesis. It also provides an insight into the effects of adaptive thermogenesis on systemic iron mobilization and redistribution.

Effect of acute cold exposure on cardiac mitochondrial function: role of sirtuins.

Cardiac function depends mainly on mitochondrial metabolism. Cold conditions increase the risk of cardiovascular diseases by increasing blood pressure. Adaptive thermogenesis leads to increased mitochondrial biogenesis and function in skeletal muscles and adipocytes. Here, we studied the effect of acute cold exposure on cardiac mitochondrial function and its regulation by sirtuins. Significant increase in mitochondrial DNA copy number as measured by the ratio between mitochondrial-coded COX-II and nuclear-coded cyclophilin A gene expression by qRT-PCR and increase in the expression of PGC-1α, a mitochondriogenic factor and its downstream target NRF-1 were observed on cold exposure. This was associated with an increase in the activity of SIRT-1, which is known to activate PGC-1α. Mitochondrial SIRT-3 was also upregulated. Increase in sirtuin activity was reflected in total protein acetylome, which decreased in cold-exposed cardiac tissue. An increase in mitochondrial MnSOD further indicated enhanced mitochondrial function. Further evidence for this was obtained from ex vivo studies of cardiac tissue treated with norepinephrine, which caused a significant increase in mitochondrial MnSOD and SIRT-3. SIRT-3 appears to mediate the regulation of MnSOD, as treatment with AGK-7, a SIRT-3 inhibitor reversed the norepinephrine-induced upregulation of MnSOD. It, therefore, appears that SIRT-3 activation in response to SIRT-1-PGC-1α activation contributes to the regulation of cardiac mitochondrial activity during acute cold exposure.

Amino acids contribute to adaptive thermogenesis. New insights into the mechanisms of action of recent drugs for metabolic disorders are emerging.

Adaptive thermogenesis is the heat production by muscle contractions (shivering thermogenesis) or brown adipose tissue (BAT) and beige fat (non-shivering thermogenesis) in response to external stimuli, including cold exposure. BAT and beige fat communicate with peripheral organs and the brain through a variegate secretory and absorption processes - controlling adipokines, microRNAs, extracellular vesicles, and metabolites - and have received much attention as potential therapeutic targets for managing obesity-related disorders. The sympathetic nervous system and norepinephrine-releasing adipose tissue macrophages (ATM) activate uncoupling protein 1 (UCP1), expressed explicitly in brown and beige adipocytes, dissolving the electrochemical gradient and uncoupling tricarboxylic acid cycle and the electron transport chain from ATP production. Mounting evidence has attracted attention to the multiple effects of dietary and endogenously synthesised amino acids in BAT thermogenesis and metabolic phenotype in animals and humans. However, the mechanisms implicated in these processes have yet to be conclusively characterized. In the present review article, we aim to define the principal investigation areas in this context, including intestinal microbiota constitution, adipose autophagy modulation, and secretome and metabolic fluxes control, which lead to increased brown/beige thermogenesis. Finally, also based on our recent epicardial adipose tissue results, we summarise the evidence supporting the notion that the new dual and triple agonists of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon (GCG) receptor - with never before seen weight loss and insulin-sensitizing efficacy - promote thermogenic-like amino acid profiles in BAT with robust heat production and likely trigger sympathetic activation and adaptive thermogenesis by controlling amino acid metabolism and ATM expansion in BAT and beige fat.

Mitophagy receptor FUNDC1 is regulated by PGC-1α/NRF1 to fine tune mitochondrial homeostasis.

Mitophagy is an essential cellular autophagic process that selectively removes superfluous and damaged mitochondria, and it is coordinated with mitochondrial biogenesis to fine tune the quantity and quality of mitochondria. Coordination between these two opposing processes to maintain the functional mitochondrial network is of paramount importance for normal cellular and organismal metabolism. However, the underlying mechanism is not completely understood. Here we report that PGC-1α and nuclear respiratory factor 1 (NRF1), master regulators of mitochondrial biogenesis and metabolic adaptation, also transcriptionally upregulate the gene encoding FUNDC1, a previously characterized mitophagy receptor, in response to cold stress in brown fat tissue. NRF1 binds to the classic consensus site in the promoter of Fundc1 to upregulate its expression and to enhance mitophagy through its interaction with LC3. Specific knockout of Fundc1 in BAT results in reduced mitochondrial turnover and accumulation of functionally compromised mitochondria, leading to impaired adaptive thermogenesis. Our results demonstrate that FUNDC1-dependent mitophagy is directly coupled with mitochondrial biogenesis through the PGC-1α/NRF1 pathway, which dictates mitochondrial quantity, quality, and turnover and contributes to adaptive thermogenesis.

Pharmacological modulation of adaptive thermogenesis: new clues for obesity management?

BACKGROUND: Adaptive thermogenesis represents the main mechanism through which the body generates heat in response to external stimuli, a phenomenon that includes shivering and non-shivering thermogenesis. The non-shivering thermogenesis is mainly exploited by adipose tissue characterized by a brown aspect, which specializes in energy dissipation. A decreased amount of brown adipose tissue has been observed in ageing and chronic illnesses such as obesity, a worldwide health problem characterized by dysfunctional adipose tissue expansion and associated cardiometabolic complications. In the last decades, the discovery of a trans-differentiation mechanism ("browning") within white adipose tissue depots, leading to the generation of brown-like cells, allowed to explore new natural and synthetic compounds able to favour this process and thus enhance thermogenesis with the aim of counteracting obesity. Based on recent findings, brown adipose tissue-activating agents could represent another option in addition to appetite inhibitors and inhibitors of nutrient absorption for obesity treatment. PURPOSE: This review investigates the main molecules involved in the physiological (e.g. incretin hormones) and pharmacological (e.g. ß3-adrenergic receptors agonists, thyroid receptor agonists, farnesoid X receptor agonists, glucagon-like peptide-1, and glucagon receptor agonists) modulation of adaptive thermogenesis and the signalling mechanisms involved.

The paradoxical lean phenotype of hypothyroid mice is marked by increased adaptive thermogenesis in the skeletal muscle.

Obesity is a major health problem worldwide, given its growing incidence and its association with a variety of comorbidities. Weight gain results from an increase in energy intake without a concomitant increase in energy expenditure. To combat the obesity epidemic, many studies have focused on the pathways underlying satiety and hunger signaling, while other studies have concentrated on the mechanisms involved in energy expenditure, most notably adaptive thermogenesis. Hypothyroidism in humans is typically associated with a decreased basal metabolic rate, lower energy expenditure, and weight gain. However, hypothyroid mouse models have been reported to have a leaner phenotype than euthyroid controls. To elucidate the mechanism underlying this phenomenon, we used a drug-free mouse model of hypothyroidism: mice lacking the sodium/iodide symporter (NIS), the plasma membrane protein that mediates active iodide uptake in the thyroid. In addition to being leaner than euthyroid mice, owing in part to reduced food intake, these hypothyroid mice show signs of compensatory up-regulation of the skeletal-muscle adaptive thermogenic marker sarcolipin, with an associated increase in fatty acid oxidation (FAO). Neither catecholamines nor thyroid-stimulating hormone (TSH) are responsible for sarcolipin expression or FAO stimulation; rather, thyroid hormones are likely to negatively regulate both processes in skeletal muscle. Our findings indicate that hypothyroidism in mice results in a variety of metabolic changes, which collectively lead to a leaner phenotype. A deeper understanding of these changes may make it possible to develop new strategies against obesity.

KMT5c modulates adipocyte thermogenesis by regulating Trp53 expression.

Brown and beige adipocytes harbor the thermogenic capacity to adapt to environmental thermal or nutritional changes. Histone methylation is an essential epigenetic modification involved in the modulation of nonshivering thermogenesis in adipocytes. Here, we describe a molecular network leading by KMT5c, a H4K20 methyltransferase, that regulates adipocyte thermogenesis and systemic energy expenditure. The expression of Kmt5c is dramatically induced by a ß3-adrenergic signaling cascade in both brown and beige fat cells. Depleting Kmt5c in adipocytes in vivo leads to a decreased expression of thermogenic genes in both brown and subcutaneous (s.c.) fat tissues. These mice are prone to high-fat-diet-induced obesity and develop glucose intolerance. Enhanced transformation related protein 53 (Trp53) expression in Kmt5c knockout (KO) mice, that is due to the decreased repressive mark H4K20me3 on its proximal promoter, is responsible for the metabolic phenotypes. Together, these findings reveal the physiological role for KMT5c-mediated H4K20 methylation in the maintenance and activation of the thermogenic program in adipocytes.

Selenium and selenoproteins in thermogenic adipocytes.

Selenium (Se) is involved in energy metabolism in the liver, white adipose tissue, and skeletal muscle, and may also play a role in thermogenic adipocytes, i.e. brown and beige adipocytes. Thereby this micronutrient is a key nutritional target to aid in combating obesity and metabolic diseases. In thermogenic adipocytes, particularly in brown adipose tissue (BAT), the selenoprotein type 2 iodothyronine deiodinase (DIO2) is essential for the activation of adaptive thermogenesis. Recent evidence has suggested that additional selenoproteins may also be participating in this process, and a role for Se itself through its metabolic pathways is also envisioned. In this review, we discuss the recognized effects and the knowledge gaps in the involvement of Se metabolism and selenoproteins in the mechanisms of adaptive thermogenesis in thermogenic (brown and beige) adipocytes.

Augmented CCL5/CCR5 signaling in brown adipose tissue inhibits adaptive thermogenesis and worsens insulin resistance in obesity.

Chemokine (C-C motif) ligand 5 (CCL5) and CCR5, one of its receptors have been reported to be highly expressed in white adipose tissue (WAT) and are associated with the progression of inflammation and the development of insulin resistance in obese humans and mice. However, the role of CCL5/CCR5 signaling in obesity-associated dysregulation of energy metabolism remains unclear. Here, we demonstrate that global CCL5/CCR5 double knockout (DKO) mice have higher cold stress-induced energy expenditure and thermogenic function in brown adipose tissue (BAT) than wildtype (WT) mice. DKO mice have higher cold stress-induced energy expenditure and thermogenic function in BAT than WT mice. KEGG pathway analysis indicated that deletion of CCL5/CCR5 further facilitated the cold-induced expression of genes related to oxidative phosphorylation (OxPhos) and lipid metabolic pathways. In primary brown adipocytes of DKO mice, the augmentation of CL-316243-stimulated thermogenic and lipolysis responses was reversed by co-treatment with AMPKα1 and α2 short interfering RNA (siRNA). Overexpression of BAT CCL5/CCR5 genes by local lentivirus injection in WT mice suppressed cold stress-induced lipolytic processes and thermogenic activities. In contrast, knockdown of BAT CCL5/CCR5 signaling further up-regulated AMPK phosphorylation as well as thermogenic and lipolysis responses to chronic adrenergic stimuli and subsequently decreased level of body weight gain. Chronic knockdown of BAT CCL5/CCR5 signaling improved high-fat diet (HFD)-induced insulin resistance in WT mice. It is suggested that obesity-induced augmentation of adipose tissue (AT) CCL5/CCR5 signaling could, at least in part, suppress energy expenditure and adaptive thermogenesis by inhibiting AMPK-mediated lipolysis and oxidative metabolism in thermogenic AT to exacerbate the development of obesity and insulin resistance.

Relation of diet-induced thermogenesis to brown adipose tissue activity in healthy men.

Human brown adipose tissue (BAT) is a thermogenic tissue activated by the sympathetic nervous system in response to cold exposure. It contributes to energy expenditure (EE) and takes up glucose and lipids from the circulation. Studies in rodents suggest that BAT contributes to the transient rise in EE after food intake, so-called diet-induced thermogenesis (DIT). We investigated the relationship between human BAT activity and DIT in response to glucose intake in 17 healthy volunteers. We assessed DIT, cold-induced thermogenesis (CIT), and maximum BAT activity at three separate study visits within 2 wk. DIT was measured by indirect calorimetry during an oral glucose tolerance test. CIT was assessed as the difference in EE after cold exposure of 2-h duration as compared with warm conditions. Maximal activity of BAT was assessed by 18-F-fluoro-deoxyglucose (18F-FDG) 18F-FDG-PET/MRI after cold exposure and concomitant pharmacological stimulation with mirabegron. Seventeen healthy men (mean age = 23.4 yr, mean body mass index = 23.2 kg/m2) participated in the study. EE increased from 1,908 (±181) kcal/24 h to 2,128 (±277) kcal/24 h (P < 0.0001, +11.5%) after mild cold exposure. An oral glucose load increased EE from 1,911 (±165) kcal/24 h to 2,096 (±167) kcal/24 h at 60 min (P < 0.0001, +9.7%). The increase in EE in response to cold was significantly associated with BAT activity (R2 = 0.43, P = 0.004). However, DIT was not associated with BAT activity (R2 = 0.015, P = 0.64). DIT after an oral glucose load was not associated with stimulated 18F-FDG uptake into BAT, suggesting that DIT is independent from BAT activity in humans (Clinicaltrials.gov Registration No. NCT03189511).NEW & NOTEWORTHY Cold-induced thermogenesis (CIT) was related to BAT activity as determined by FDG-PET/MRI after stimulation of BAT. Diet-induced thermogenesis (DIT) was not related to stimulated BAT activity. Supraclavicular skin temperature was related to CIT but not to DIT. DIT in humans is probably not a function of BAT.

Dietary Iron Deficiency Modulates Adipocyte Iron Homeostasis, Adaptive Thermogenesis, and Obesity in C57BL/6 Mice.

BACKGROUND: Adaptive thermogenesis is an iron-demanding pathway, significantly contributing to whole-body energy expenditure. However, the effects of iron-deficient diets on adaptive thermogenesis and obesity remain unknown. OBJECTIVES: We aimed to determine the impact of dietary iron deficiency on iron homeostasis in adipocytes, adaptive thermogenic capacity, and metabolic consequences in obesity. METHODS: C57BL/6 male mice were assigned to either the iron-adequate (IA, 35 ppm) or the iron-deficient group (ID, 3 ppm) at weaning. Upon 8 wk of age, both IA and ID groups received an isocaloric high-fat diet (45% kcal from fat) for 10 wk, maintaining the same iron content. Mice (n = 8) were used to determine the iron status at the systemic and tissue levels and lipid metabolism and inflammatory signaling in adipose tissue. The same mice were used to evaluate cold tolerance (4°C) for 3 h. For assessing adaptive thermogenesis, mice (n = 5) received an intraperitoneal injection of ß3-adrenoceptor agonist CL316243 (CL) for 5 d. RESULTS: Compared with the IA group, the ID group had nonanemic iron deficiency, lower serum ferritin (42.8%, P < 0.01), and greater weight gain (8.67%, P < 0.05) and insulin resistance (159%, P < 0.01), partly due to reduced AMP-activated protein kinase activation (61.0%, P < 0.05). Upon cold exposure, the ID group maintained a core body temperature 2°C lower than the IA group. The ID group had lower iron content (47.0%, P < 0.01) in the inguinal adipose tissue (iWAT) than the IA group, which was associated with impaired adaptive thermogenesis. In response to CL, ID mice showed decreased heat production (P < 0.01) and defective upregulation of beige adipocyte-specific markers, including uncoupling protein 1 (41.1%, P < 0.001), transferrin receptor 1 (47.5%, P < 0.001), and mitochondrial respiratory chain complexes (P < 0.05) compared with IA mice. CONCLUSIONS: Dietary iron deficiency deregulates iron balance in the iWAT and impairs adaptive thermogenesis, thereby escalating the diet-induced weight gain in C57BL/6 mice.

A restricted cafeteria diet ameliorates biometric and metabolic profile in a rat diet-induced obesity model.

The administration of anti-obesity bioactive compounds and/or functional foods in rodents fed energy restriction diets based on chow food can be difficult to interpret. We propose an energy restricted cafeteria (CAF) diet as a dietetic intervention to be combined with other therapies. Postweaning male rats were fed standard chow, CAF diet or 30% energy restricted CAF diet (CAF-R) for 8 weeks. The CAF-R diet lowered energy intake and the increase of body weight and body mass index due to the CAF diet, lead to an intermediate feed efficiency, and dampened the CAF diet-induced alterations on body composition, serum levels of triacylglycerides and NEFAs, and insulin resistance. These effects were associated with diminished Ucp1, Nrf1 and Tfam1 gene expression in brown adipose tissue. In conclusion, the CAF-R diet ameliorated obesity and related metabolic disorders induced by a regular CAF diet, turning it in a useful tool to study anti-obesity compounds.

Taurine-mediated browning of white adipose tissue is involved in its anti-obesity effect in mice.

Taurine, a nonprotein amino acid, is widely distributed in almost all animal tissues. Ingestion of taurine helps to improve obesity and its related metabolic disorders. However, the molecular mechanism underlying the protective role of taurine against obesity is not completely understood. In this study, it was found that intraperitoneal treatment of mice with taurine alleviated high-fat diet (HFD)-induced obesity, improved insulin sensitivity, and increased energy expenditure and adaptive thermogenesis of the mice. Meanwhile, administration of the mice with taurine markedly induced the browning of inguinal white adipose tissue (iWAT) with significantly elevated expression of PGC1α, UCP1, and other thermogenic genes in iWAT. In vitro studies indicated that taurine also induced the development of brown-like adipocytes in C3H10T1/2 white adipocytes. Knockdown of PGC1α blunted the role of taurine in promoting the brown-like adipocyte phenotypes in C3H10T1/2 cells. Moreover, taurine treatment enhanced AMPK phosphorylation in vitro and in vivo, and knockdown of AMPKα1 prevented taurine-mediated induction of PGC1α in C3H10T1/2 cells. Consistently, specific knockdown of PGC1α in iWAT of the HFD-fed mice inhibited taurine-induced browning of iWAT, with the role of taurine in the enhancement of adaptive thermogenesis, the prevention of obesity, and the improvement of insulin sensitivity being partially impaired. These results reveal a functional role of taurine in facilitating the browning of white adipose tissue, which depends on the induction of PGC1α. Our studies also suggest a potential mechanism for the protective role of taurine against obesity, which involves taurine-mediated browning of white adipose tissue.

Chronic arsenic exposure impairs adaptive thermogenesis in male C57BL/6J mice.

The global prevalence of type 2 diabetes (T2D) has doubled since 1980. Human epidemiological studies support arsenic exposure as a risk factor for T2D, although the precise mechanism is unclear. We hypothesized that chronic arsenic ingestion alters glucose homeostasis by impairing adaptive thermogenesis, i.e., body heat production in cold environments. Arsenic is a pervasive environmental contaminant, with more than 200 million people worldwide currently exposed to arsenic-contaminated drinking water. Male C57BL/6J mice exposed to sodium arsenite in drinking water at 300 µg/L for 9 wk experienced significantly decreased metabolic heat production when acclimated to chronic cold tolerance testing, as evidenced by indirect calorimetry, despite no change in physical activity. Arsenic exposure increased total fat mass and subcutaneous inguinal white adipose tissue (iWAT) mass. RNA sequencing analysis of iWAT indicated that arsenic dysregulated mitochondrial processes, including fatty acid metabolism. Western blotting in WAT confirmed that arsenic significantly decreased TOMM20, a correlate of mitochondrial abundance; PGC1A, a master regulator of mitochondrial biogenesis; and, CPT1B, the rate-limiting step of fatty acid oxidation (FAO). Our findings show that chronic arsenic exposure impacts the mitochondrial proteins of thermogenic tissues involved in energy expenditure and substrate regulation, providing novel mechanistic evidence for arsenic's role in T2D development.

High Compared with Moderate Protein Intake Reduces Adaptive Thermogenesis and Induces a Negative Energy Balance during Long-term Weight-Loss Maintenance in Participants with Prediabetes in the Postobese State: A PREVIEW Study.

BACKGROUND: Weight loss has been associated with adaptations in energy expenditure. Identifying factors that counteract these adaptations are important for long-term weight loss and weight maintenance. OBJECTIVE: The aim of this study was to investigate whether increased protein/carbohydrate ratio would reduce adaptive thermogenesis (AT) and the expected positive energy balance (EB) during weight maintenance after weight loss in participants with prediabetes in the postobese state. METHODS: In 38 participants, the effects of 2 diets differing in protein/carbohydrate ratio on energy expenditure and respiratory quotient (RQ) were assessed during 48-h respiration chamber measurements ∼34 mo after weight loss. Participants consumed a high-protein (HP) diet (n = 20; 13 women/7 men; age: 64.0 ± 6.2 y; BMI: 28.9 ± 4.0 kg/m 2) with 25:45:30% or a moderate-protein (MP) diet (n = 18; 9 women/9 men; age: 65.1 ± 5.8 y; BMI: 29.0 ± 3.8 kg/m 2) with 15:55:30% of energy from protein:carbohydrate:fat. Predicted resting energy expenditure (REEp) was calculated based on fat-free mass and fat mass. AT was assessed by subtracting measured resting energy expenditure (REE) from REEp. The main outcomes included differences in components of energy expenditure, substrate oxidation, and AT between groups. RESULTS: EB (MP = 0.2 ± 0.9 MJ/d; HP = -0.5 ± 0.9 MJ/d) and RQ (MP = 0.84 ± 0.02; HP = 0.82 ± 0.02) were reduced and REE (MP: 7.3 ± 0.2 MJ/d compared with HP: 7.8 ± 0.2 MJ/d) was increased in the HP group compared with the MP group (P < 0.05). REE was not different from REEp in the HP group, whereas REE was lower than REEp in the MP group (P < 0.05). Furthermore, EB was positively related to AT (rs = 0.74; P < 0.001) and RQ (rs = 0.47; P < 0.01) in the whole group of participants. CONCLUSIONS: In conclusion, an HP diet compared with an MP diet led to a negative EB and counteracted AT ∼34 mo after weight loss, in participants with prediabetes in the postobese state. These results indicate the relevance of compliance to an increased protein/carbohydrate ratio for long-term weight maintenance after weight loss. The trial was registered at clinicaltrials.gov as NCT01777893.

Regulator of Calcineurin 1 helps coordinate whole-body metabolism and thermogenesis.

Increasing non-shivering thermogenesis (NST), which expends calories as heat rather than storing them as fat, is championed as an effective way to combat obesity and metabolic disease. Innate mechanisms constraining the capacity for NST present a fundamental limitation to this approach, yet are not well understood. Here, we provide evidence that Regulator of Calcineurin 1 (RCAN1), a feedback inhibitor of the calcium-activated protein phosphatase calcineurin (CN), acts to suppress two distinctly different mechanisms of non-shivering thermogenesis (NST): one involving the activation of UCP1 expression in white adipose tissue, the other mediated by sarcolipin (SLN) in skeletal muscle. UCP1 generates heat at the expense of reducing ATP production, whereas SLN increases ATP consumption to generate heat. Gene expression profiles demonstrate a high correlation between Rcan1 expression and metabolic syndrome. On an evolutionary timescale, in the context of limited food resources, systemic suppression of prolonged NST by RCAN1 might have been beneficial; however, in the face of caloric abundance, RCAN1-mediated suppression of these adaptive avenues of energy expenditure may now contribute to the growing epidemic of obesity.

Estrogen-Related Receptor Alpha: An Under-Appreciated Potential Target for the Treatment of Metabolic Diseases.

The estrogen-related receptor alpha (ESRRA) is an orphan nuclear receptor (NR) that significantly influences cellular metabolism. ESRRA is predominantly expressed in metabolically-active tissues and regulates the transcription of metabolic genes, including those involved in mitochondrial turnover and autophagy. Although ESRRA activity is well-characterized in several types of cancer, recent reports suggest that it also has an important role in metabolic diseases. This minireview focuses on the regulation of cellular metabolism and function by ESRRA and its potential as a target for the treatment of metabolic disorders.

Dietary apple polyphenols promote fat browning in high-fat diet-induced obese mice through activation of adenosine monophosphate-activated protein kinase α.

BACKGROUND: Promoting brown and beige adipogenesis contributes to adaptive thermogenesis, which provides a defense against obesity and related disorders. Apple polyphenols (APs) play a significant role in treating variety of metabolic diseases. This study was conducted to determine the effects of APs on the development of brown and beige adipocytes and thermogenesis and investigate whether these effects are mediated by adenosine monophosphate-activated protein kinase (AMPK). High-fat diet (HFD)-induced obese mice and differentiated 3T3-L1 adipocytes were subjected to APs treatment. The thermogenic program and associated regulatory factors, and the involvement of AMPKα was assessed. RESULTS: Dietary APs supplementation reduced adiposity and improved insulin sensitivity in HFD-induced obese mice. Moreover, APs increased the oxygen consumption and heat production and decreased respiratory exchange ratio, which were accompanied by the upregulation of thermogenic genes expression and the activation of AMPKα in brown fat and inguinal white fat. Further, APs treatment directly increased expression of brown adipogenic markers and induced phosphorylation of AMPKα in differentiated 3T3-L1 adipocytes, whereas the beneficial effects of APs were reversed by AMPK inhibition. CONCLUSION: Our results provide new insights into the function of APs in regulating brown/beige adipogenesis and adaptive thermogenesis and suggest the potential application of APs in the prevention and therapeutics of obesity and associated metabolic diseases. © 2020 Society of Chemical Industry.