BAT Thermogenesis Research Articles

Sympathetic innervation of interscapular brown adipose tissue is not a predominant mediator of OT-elicited reductions of body weight gain and adiposity in male diet-induced obese rats.

Recent studies indicate that central administration of oxytocin (OT) reduces body weight (BW) in high fat diet-induced obese (DIO) rodents by reducing energy intake and increasing energy expenditure (EE). Previous studies in our lab have shown that administration of OT into the fourth ventricle (4V; hindbrain) elicits weight loss and stimulates interscapular brown adipose tissue temperature (TIBAT) in DIO rats. We hypothesized that OT-elicited stimulation of sympathetic nervous system (SNS) activation of IBAT contributes to its ability to activate BAT and reduce BW in DIO rats. To test this, we determined the effect of disrupting SNS activation of IBAT on OT-elicited stimulation of TIBAT and reduction of BW in DIO rats. We first confirmed that bilateral surgical SNS denervation to IBAT was successful based on having achieved ≥ 60% reduction in IBAT norepinephrine (NE) content from DIO rats. NE content was selectively reduced in IBAT by 94.7 ± 2.7, 96.8 ± 1.8 and 85.9 ± 6.1% (P<0.05) at 1, 6 and 7-weeks post-denervation, respectively, and was unchanged in liver or inguinal white adipose tissue. We then measured the impact of bilateral surgical SNS denervation to IBAT on the ability of acute 4V OT (1, 5 μg) to stimulate TIBAT in DIO rats. We found that the high dose of 4V OT (5 μg) stimulated TIBAT similarly between sham and denervated rats (P=NS) and that the effects of 4V OT to stimulate TIBAT did not require beta-3 adrenergic receptor signaling. We subsequently measured the effect of bilateral surgical denervation of IBAT on the effect of chronic 4V OT (16 nmol/day) or vehicle infusion to reduce BW, adiposity and energy intake in DIO rats. Chronic 4V OT reduced BW gain by -7.2 ± 9.6 g and -14.1 ± 8.8 g in sham and denervated rats (P<0.05 vs vehicle treatment), respectively, and this effect was similar between groups (P=NS). These effects were associated with reductions in adiposity and energy intake (P<0.05). Collectively, these findings support the hypothesis that sympathetic innervation of IBAT is not required for central OT to increase BAT thermogenesis and reduce BW gain and adiposity in male DIO rats.

Sympathetic innervation of interscapular brown adipose tissue is not a predominant mediator of oxytocin-elicited reductions of body weight and adiposity in male diet-induced obese mice.

Previous studies indicate that CNS administration of oxytocin (OT) reduces body weight in high fat diet-induced obese (DIO) rodents by reducing food intake and increasing energy expenditure (EE). We recently demonstrated that hindbrain (fourth ventricular [4V]) administration of OT elicits weight loss and elevates interscapular brown adipose tissue temperature (TIBAT, a surrogate measure of increased EE) in DIO mice. What remains unclear is whether OT-elicited weight loss requires increased sympathetic nervous system (SNS) outflow to IBAT. We hypothesized that OT-induced stimulation of SNS outflow to IBAT contributes to its ability to activate BAT and elicit weight loss in DIO mice. To test this hypothesis, we determined the effect of disrupting SNS activation of IBAT on the ability of 4V OT administration to increase TIBAT and elicit weight loss in DIO mice. We first determined whether bilateral surgical SNS denervation to IBAT was successful as noted by ≥ 60% reduction in IBAT norepinephrine (NE) content in DIO mice. NE content was selectively reduced in IBAT at 1-, 6- and 7-weeks post-denervation by 95.9 ± 2.0, 77.4 ± 12.7 and 93.6 ± 4.6% (P<0.05), respectively and was unchanged in inguinal white adipose tissue, pancreas or liver. We subsequently measured the effects of acute 4V OT (1, 5 µg ≈ 0.99, 4.96 nmol) on TIBAT in DIO mice following sham or bilateral surgical SNS denervation to IBAT. We found that the high dose of 4V OT (5 µg ≈ 4.96 nmol) elevated TIBAT similarly in sham mice as in denervated mice. We subsequently measured the effects of chronic 4V OT (16 nmol/day over 29 days) or vehicle infusions on body weight, adiposity and food intake in DIO mice following sham or bilateral surgical denervation of IBAT. Chronic 4V OT reduced body weight by 5.7 ± 2.23% and 6.6 ± 1.4% in sham and denervated mice (P<0.05), respectively, and this effect was similar between groups (P=NS). OT produced corresponding reductions in whole body fat mass (P<0.05). Together, these findings support the hypothesis that sympathetic innervation of IBAT is not necessary for OT-elicited increases in BAT thermogenesis and reductions of body weight and adiposity in male DIO mice.

Sympathetic innervation of interscapular brown adipose tissue is not a predominant mediator of oxytocin-elicited reductions of body weight and adiposity in male diet-induced obese mice.

Previous studies indicate that CNS administration of oxytocin (OT) reduces body weight in high fat diet-induced obese (DIO) rodents by reducing food intake and increasing energy expenditure (EE). We recently demonstrated that hindbrain (fourth ventricular [4V]) administration of OT elicits weight loss and elevates interscapular brown adipose tissue temperature (T IBAT , a surrogate measure of increased EE) in DIO mice. What remains unclear is whether OT-elicited weight loss requires increased sympathetic nervous system (SNS) outflow to IBAT. We hypothesized that OT-induced stimulation of SNS outflow to IBAT contributes to its ability to activate BAT and elicit weight loss in DIO mice. To test this hypothesis, we determined the effect of disrupting SNS activation of IBAT on the ability of 4V OT administration to increase T IBAT and elicit weight loss in DIO mice. We first determined whether bilateral surgical SNS denervation to IBAT was successful as noted by ≥ 60% reduction in IBAT norepinephrine (NE) content in DIO mice. NE content was selectively reduced in IBAT at 1-, 6- and 7-weeks post-denervation by 95.9±2.0, 77.4±12.7 and 93.6±4.6% ( P <0.05), respectively and was unchanged in inguinal white adipose tissue, pancreas or liver. We subsequently measured the effects of acute 4V OT (1, 5 µg ≈ 0.99, 4.96 nmol) on T IBAT in DIO mice following sham or bilateral surgical SNS denervation to IBAT. We found that the high dose of 4V OT (5 µg ≈ 4.96 nmol) elevated T IBAT similarly in sham mice as in denervated mice. We subsequently measured the effects of chronic 4V OT (16 nmol/day over 29 days) or vehicle infusions on body weight, adiposity and food intake in DIO mice following sham or bilateral surgical denervation of IBAT. Chronic 4V OT reduced body weight by 5.7±2.23% and 6.6±1.4% in sham and denervated mice ( P <0.05), respectively, and this effect was similar between groups ( P =NS). OT produced corresponding reductions in whole body fat mass ( P <0.05). Together, these findings support the hypothesis that sympathetic innervation of IBAT is not necessary for OT-elicited increases in BAT thermogenesis and reductions of body weight and adiposity in male DIO mice.

UCP1 and CKB are parallel players in BAT

It is generally believed that the contributions of the UCP1-independent thermogenic pathways are secondary to UCP1-mediated thermogenesis in BAT. Now, Rahbani etal. demonstrate invivo that adaptive thermogenesis in brown adipose tissue is regulated by UCP1 and CKB in parallel.

Conjugated linoleic acid (CLA) reduces HFD-induced obesity by enhancing BAT thermogenesis and iWAT browning via the CD36-AMPK pathway.

The antiobesity effect of conjugated linoleic acid (CLA) has been reported. However, the underlying mechanisms have not been fully clarified. Thus, this study aimed to investigate the effects of CLA on thermogenesis of interscapular brown adipose tissue (iBAT) and browning of inguinal subcutaneous white adipose tissue (iWAT) and explore the possible signaling pathway. The in vivo results showed that CLA enhanced the O2 consumption and heat production in HFD (high-fat diet)-fed female mice by roughly 38%. Meanwhile, CLA increased the average iBAT temperature by 2°C at the room temperature and cold exposure, respectively. Correspondingly, CLA caused 1.6-and 2.4-fold increases in the expression of UCP1 (uncoupling protein 1) of BAT and iWAT, respectively, suggesting the activated iBAT thermogenesis and iWAT browning in HFD-fed female mice. Meanwhile, CLA could promote the formation of brown and beige adipocytes in differentiated stromal vascular cells (SVCs) isolated from iBAT and iWAT (the expressions of UCP1 were promoted by about twofold changes). In possible mechanisms, CLA stimulated the expression of CD36 and the activation of theAMPK pathway in mice iBAT and iWAT as well as the differentiated SVCs. However, inhibition of CD36 and AMPK (adenosine 5'-monophosphate-activated protein kinase) abolished the promotive effects of CLA on brown and beige adipocytes formation. Hence, we showed that CLA reduced HFD-induced obesity through enhancing iBAT thermogenesis and iWAT browning via theCD36-AMPK pathway.

Brown adipose Vanin-1 is required for the maintenance of mitochondrial homeostasis and prevents diet-induced metabolic dysfunction

BackgroundEnergy-dissipating brown adipocytes have significant potential for improving systemic metabolism. Vanin-1, a membrane-bound pantetheinase, is involved in various biological processes in mice. However, its role in BAT mitochondrial function is still unclear. In this study, we aimed to elucidate the impact of Vanin-1 on BAT function and contribution during overnutrition-induced obesity. MethodsVanin-1 expression was analyzed in different adipose depots in mice. The cellular localization of Vanin-1 was analyzed by confocal microscopy and western blots. Mice lacking Vanin-1 (Vanin-1−/−) were continuously fed either a chow diet or a high-fat diet (HFD) to establish an obesity model. RNA-seq analysis was performed to identify the molecular changes associated with Vanin-1 deficiency during obesity. BAT-specific Vanin-1 overexpression mice were established to determine the effects of Vanin-1 in vivo. Cysteamine treatment was used to examine the effect of enzymatic reaction products of Vanin-1 on BAT mitochondria function in Vanin-1−/− mice. ResultsThe results indicate that the expression of Vanin-1 is reduced in BAT from both diet-induced and leptin-deficient obese mice. Study on the subcellular location of Vanin-1 shows that it has a mitochondrial localization. Vanin-1 deficiency results in increased adiposity, BAT dysfunction, aberrant mitochondrial structure, and promotes HFD induced-BAT whitening. This is attributed to the impairment of the electron transport chain (ETC) in mitochondria due to Vanin-1 deficiency, resulting in reduced mitochondrial respiration. Overexpression of Vanin-1 significantly enhances energy expenditure and thermogenesis in BAT, renders mice resistant to diet-induced obesity. Furthermore, treatment with cysteamine rescue the mitochondrial dysfunction in Vanin-1−/− mice. ConclusionsCollectively, these findings suggest that Vanin-1 plays a crucial role in promoting mitochondrial respiration to counteract diet-induced obesity, making it a potential therapeutic target for obesity.

Differential effects of milk, yogurt, and cheese on energy homeostasis and brown adipose tissue phenotype in high-fat diet-induced obese mice.

Aim: We hypothesized that milk, yogurt, and cheese have differential impacts on energy expenditure (EE) and obesity in mice fed a high-fat diet (HFD). Methods: C57BL/6 mice (n = 16 per group) were fed a HFD or a HFD supplemented with fat-free milk (MILK), fat-free plain yogurt (YOG), or reduced-fat cheddar cheese (CHE; 19 kcal% fat), each provided at 10% of the daily energy intake, for 8 weeks. EE was quantified using a metabolic chamber. Metabolic pathways related to BAT mitochondrial function and uncoupling protein 1 (UCP1) abundance were assessed. Serum lipidomic profiles were analyzed to identify potential mediators of the observed effects. Results: MILK supplementation lowered weight gain and fat accumulation and enhanced EE and BAT thermogenesis, perhaps via the SIRT1-AMPK-PGC1α axis in BAT. This led to elevated UCP1 abundance and enhanced the abundance of hormone-sensitive lipase (HSL). MILK also altered serum lipid species, indicating enhanced energy use, and promoted BAT thermogenesis and mitochondrial function pathways. YOG exhibited a similar pattern but a lower magnitude of effects than MILK on reducing weight gain and fat mass, increasing EE, and BAT thermogenic proteins, including AMPK-PGC1α-UCP1. Both MILK and YOG showed a relative increase in serum PC 15:0_15:0 and LPC 15:0. In contrast, CHE reduced weight gain and increased EE without impacting BAT thermogenesis proteins or serum lipid species. Conclusion: Our study showed that MILK, YOG, and CHE reduced weight gain in mice on a HFD by increasing EE. MILK and YOG also up-regulated BAT thermogenesis, while both additionally altered lipids involved in fat metabolism and inflammation. CHE did not affect BAT thermogenesis and lipid species compared to HFD.

CXCL13 promotes thermogenesis in mice via recruitment of M2 macrophage and inhibition of inflammation in brown adipose tissue.

Brown adipose tissue (BAT) is mainly responsible for mammalian non-shivering thermogenesis and promotes energy expenditure. Meanwhile, similar to white adipose tissue (WAT), BAT also secretes a variety of adipokines to regulate metabolism through paracrine, autocrine, or endocrine ways. The chemokine C-X-C motif chemokine ligand-13 (CXCL13), a canonical B cell chemokine, functions in inflammation and tumor-related diseases. However, the role of CXCL13 in the adipose tissues is unclear. The expression of CXCL13 in BAT and subcutaneous white adipose tissue (SWAT) of mice under cold stimulation were detected. Local injection of CXCL13 into BAT of normal-diet and high-fat-diet induced obese mice was used to detect thermogenesis and determine cold tolerance. The brown adipocytes were treated with CXCL13 alone or in the presence of macrophages to determine the effects of CXCL13 on thermogenic and inflammation related genes expression in vitro. In this study, we discovered that the expression of CXCL13 in the stromal cells of brown adipose tissue significantly elevated under cold stimulation. Overexpression of CXCL13 in the BAT via local injection could increase energy expenditure and promote thermogenesis in obese mice. Mechanically, CXCL13 could promote thermogenesis via recruiting M2 macrophages in the BAT and, in the meantime, inhibiting pro-inflammatory factor TNFα level. This study revealed the novel role of adipose chemokine CXCL13 in the regulation of BAT activity and thermogenesis.

Extracts of Dunkelfelder Grape Seeds and Peel Increase the Metabolic Rate and Reduce Fat Deposition in Mice Maintained on a High-Fat Diet.

Chronic high-fat diet intake may induce obesity and increase the risk of metabolic syndrome. The pomace of grape (Vitis vinifera L.) is rich in polyphenols, which are candidates for anti-obesity therapy. The present study aimed to investigate the effects of Dunkelfelder grape seed extract (GSE) and grape peel extract (GPE) on lipid and energy metabolism disorders in mice maintained on a high-fat diet (HFD). Male nine-week C57BL/6J mice were randomly assigned to one of four groups, namely, the normal chow diet (ND), HFD, HFD plus GSE (400 mg/kg BW) administered by oral gavage, or HFD plus GPE (400 mg/kg BW) administered by oral gavage. There were eight mice per group, and the experiment was 14 weeks in duration. The results showed that GSE and GPE treatments did not affect energy intake in mice on a high-fat diet, but body weight gain was 24.5% and 17.3% lower in the GSE- and GPE-treated mice than in the HFD group, respectively. They also decreased blood triglyceride (TG), total cholesterol (TC), and fasting blood glucose levels and increased high-density lipoprotein cholesterol (HDL-C). In addition, GSE and GPE reduced adipose tissue weight and excessive lipid droplet accumulation in the adipocytes. The metabolic chamber test showed that the GSE and GPE treatments enhanced oxygen consumption, carbon dioxide production, and heat release while decreasing the respiratory exchange rate (RER). This suggests that GSE and GPE augmented fuel oxidation and energy generation and increased the proportion of lipids being utilized in energy metabolism. GSE and GPE also upregulated the genes controlling lipolysis and downregulated those controlling lipogenesis in adipose tissues. Moreover, they significantly increased the expression levels of the genes regulating thermogenesis in BAT, eWAT, and iWAT, and mitochondrial biogenesis in all three types of adipose tissue. In conclusion, the present study empirically demonstrated that GSE and GPE enhance body fat utilization by augmenting lipid and energy metabolism and could, therefore, ameliorate high-fat diet-induced obesity.

Proline hydroxylase 2 (PHD2) promotes brown adipose thermogenesis by enhancing the hydroxylation of UCP1

ObjectiveBrown adipose tissue (BAT) plays a crucial role in regulating non-shivering thermogenesis under cold exposure. Proline hydroxylases (PHDs) were found to be involved in adipocyte differentiation and lipid deposition. However, the effects of PHDs on regulatory mechanisms of BAT thermogenesis are not fully understood. MethodsWe detected the expression of PHDs in different adipose tissues by using immunoblotting and real-time PCR. Further, immunoblotting, real-time PCR, and immunostaining were performed to determine the correlation between proline hydroxylase 2 (PHD2) and UCP1 expression. Inhibitor of PHDs and PHD2-sgRNA viruses were used to construct the PHD2-deficiency model in vivo and in vitro to investigate the impacts of PHD2 on BAT thermogenesis. Afterward, the interaction between UCP1 and PHD2 and the hydroxylation modification level of UCP1 were verified by Co-IP assays and immunoblotting. Finally, the effect of specific proline hydroxylation on the expression/activity of UCP1 was further confirmed by site-directed mutation of UCP1 and mass spectrometry analysis. ResultsPHD2, but not PHD1 and PHD3, was highly enriched in BAT, colocalized, and positively correlated with UCP1. Inhibition or knockdown of PHD2 significantly suppressed BAT thermogenesis under cold exposure and aggravated obesity of mice fed HFD. Mechanistically, mitochondrial PHD2 bound to UCP1 and regulated the hydroxylation level of UCP1, which was enhanced by thermogenic activation and attenuated by PHD2 knockdown. Furthermore, PHD2-dependent hydroxylation of UCP1 promoted the expression and stability of UCP1 protein. Mutation of the specific prolines (Pro-33, 133, and 232) in UCP1 significantly mitigated the PHD2-elevated UCP1 hydroxylation level and reversed the PHD2-increased UCP1 stability. ConclusionsThis study suggested an important role for PHD2 in BAT thermogenesis regulation by enhancing the hydroxylation of UCP1.

Reduced hepatic bradykinin degradation accounts for cold-induced BAT thermogenesis and WAT browning in male mice

An important role for liver in the regulation of adipose tissue thermogenesis upon cold exposure has been suggested; however, the underlying mechanisms remain incompletely defined. Here, we identify elevated serum bradykinin levels in response to acute cold exposure in male mice. A bolus of anti-bradykinin antibodies reduces body temperature during acute cold exposure, whereas bradykinin has the opposite effect. We demonstrate that bradykinin induces brown adipose tissue thermogenesis and white adipose tissue browning, and bradykinin increases uncoupling protein 1 (UCP1) expression in adipose tissue. The bradykinin B2 receptor (B2R), adrenergic signaling and nitric oxide signaling are involved in regulating bradykinin-increased UCP1 expression. Moreover, acute cold exposure inhibits hepatic prolyl endopeptidase (PREP) activity, causing reduced liver bradykinin degradation and increased serum bradykinin levels. Finally, by blocking the breakdown of bradykinin, angiotensin-converting enzyme inhibitors (ACEIs) increase serum bradykinin levels and induce brown adipose tissue thermogenesis and white adipose tissue browning via B2R. Collectively, our data provide new insights into the mechanisms underlying organ crosstalk in whole-body physiology control during cold exposure and also suggest bradykinin as a possible anti-obesity target.

The hyperthermic response to intra-preoptic area administration of agmatine in male rats

Agmatine is an endogenous biogenic amine that exerts various effects on the central nervous system. The hypothalamic preoptic area (POA, thermoregulatory command center) has high agmatine immunoreactivity. In this study, in conscious and anesthetized male rats, agmatine microinjection into the POA induced hyperthermic responses associated with increased heat production and locomotor activity. Intra-POA administration of agmatine increased the locomotor activity, the brown adipose tissue temperature and rectum temperature, and induced shivering as demonstrated by increased neck muscle electromyographic activity. However, intra-POA administration of agmatine almost had no impact on the tail temperature of anesthetized rats. Furthermore, there were regional differences in the response to agmatine in the POA. The most effective sites for the microinjection of agmatine to elicit hyperthermic responses were localized in the medial preoptic area (MPA). Agmatine microinjection into the median preoptic nucleus (MnPO) and lateral preoptic nucleus (LPO) had a minimal effect on the mean core temperature. Analysis of the in vitro discharge activity of POA neurons in brain slices when perfused with agmatine showed that agmatine inhibited most warm-sensitive but not temperature-insensitive neurons in the MPA. However, regardless of thermosensitivity, the majority of MnPO and LPO neurons were not responsive to agmatine. The results demonstrated that agmatine injection into the POA of male rats, especially the MPA, induced hyperthermic responses, which may be associated with increased BAT thermogenesis, shivering and locomotor activity by inhibiting warm-sensitive neurons.

Long-term exposure to low-dose Di(2-ethylhexyl) phthalate aggravated high fat diet-induced obesity in female mice

The potential obesogenic roles of di(2-ethylhexyl) phthalate (DEHP) have attracted great attention. The current study aimed to evaluate the combined effects of chronic low-dose DEHP (0.05 mg/kg BW) and a high-fat diet (HFD) on obesity in female mice and explore the underlying mechanisms. We found that low-dose DEHP challenge for 29 weeks increased fat accumulation both in CD- and HFD-fed mice and significantly accelerated the weight gain without affecting food intake in HFD-fed mice. DEHP exposure reduced the energy metabolism, down-regulated the uncoupling protein 1 (UCP1) and total oxidative phosphorylation (OXPHOS) proteins expression in the brown adipose tissue, and up-regulated the PPARγ expression and its phosphorylation at Ser273 in white adipose tissue (WAT). Besides, the combination of DEHP and HFD drove the remodeling of gut microbiota of mice, characterized by the reduced richness and diversity and the elevated Firmicutes to Bacteroidetes (F/B) ratio. Short-chain fatty acids (SCFAs) analysis revealed that DEHP and HFD cotreatment led to a decrease in levels of acetic acid, butyric acid, and pentanoic acid. Interestingly, sodium butyrate (NaB) significantly inhibited the adipogenesis and lipid accumulation of NIH/3T3 mouse embryonic fibroblasts (PPARγ2 overexpression) and the PPARγ phosphorylation at Ser273 induced by DEHP or MEHP. These findings demonstrate that chronic low-dose DEHP challenge could prompt fat accumulation by increasing PPARγ phosphorylation at Ser273 and decreasing thermogenesis in BAT, which might be associated with the SCFAs reduction.

Myeloid p38 activation maintains macrophage-liver crosstalk and BAT thermogenesis through IL-12-FGF21 axis.

Obesity features excessive fat accumulation in several body tissues and induces a state of chronic low-grade inflammation that contributes to the development of diabetes, steatosis, and insulin resistance. Recent research has shown that this chronic inflammation is crucially dependent on p38 pathway activity in macrophages, suggesting p38 inhibition as a possible treatment for obesity comorbidities. Nevertheless, we report here that lack of p38 activation in myeloid cells worsens high-fat diet-induced obesity, diabetes, and steatosis. Deficient p38 activation increases macrophage IL-12 production, leading to inhibition of hepatic FGF21 and reduction of thermogenesis in the brown fat. The implication of FGF21 in the phenotype was confirmed by its specific deletion in hepatocytes. We also found that IL-12 correlates with liver damage in human biopsies, indicating the translational potential of our results. Our findings suggest that myeloid p38 has a dual role in inflammation and that drugs targeting IL-12 might improve the homeostatic regulation of energy balance in response to metabolic stress.

Central Regulation of Brown Fat Thermogenesis in Response to Saturated or Unsaturated Long-Chain Fatty Acids.

Sensing of long-chain fatty acids (LCFA) in the hypothalamus modulates energy balance, and its disruption leads to obesity. To date, the effects of saturated or unsaturated LCFA on hypothalamic-brown adipose tissue (BAT) axis and the underlying mechanisms have remained largely unclear. Our aim was to characterize the main molecular pathways involved in the hypothalamic regulation of BAT thermogenesis in response to LCFA with different lengths and degrees of saturation. One-week administration of high-fat diet enriched in monounsaturated FA led to higher BAT thermogenesis compared to a saturated FA-enriched diet. Intracerebroventricular infusion of oleic and linoleic acids upregulated thermogenesis markers and temperature in brown fat of mice, and triggered neuronal activation of paraventricular (PaV), ventromedial (VMH) and arcuate (ARC) hypothalamic nuclei, which was not found with saturated FAs. The neuron-specific protein carnitine palmitoyltransferase 1-C (CPT1C) was a crucial effector of oleic acid since the FA action was blunted in CPT1C-KO mice. Moreover, changes in the AMPK/ACC/malonyl-CoA pathway and fatty acid synthase expression were evoked by oleic acid. Altogether, central infusion of unsaturated but not saturated LCFA increases BAT thermogenesis through CPT1C-mediated sensing of FA metabolism shift, which in turn drive melanocortin system activation. These findings add new insight into neuronal circuitries activated by LCFA to drive thermogenesis.

Mother’s warmth from maternal genes: genomic imprinting of brown adipose tissue

Abstract Background and objectives Brown adipose tissue (BAT) plays key roles in mammalian physiology, most notably with regard to thermoregulation in infants and juveniles. Previous studies have suggested that intragenomic conflict, in the form of genomic imprinting, mediates BAT thermogenesis, because it represents a public good for groups of siblings, or a mother with her offspring, who huddle together to conserve warmth. By this hypothesis, maternally expressed imprinted genes should promote BAT, while paternally expressed genes should repress it. Methodology We systematically searched the literature using two curated lists of genes imprinted in humans and/or mice, in association with evidence regarding effects of perturbation to imprinted gene expression on BAT development or activity. Results Overall, enhanced BAT was associated with relatively higher expression of maternally expressed imprinted genes, and relatively lower expression of paternally expressed imprinted genes; this pattern was found for 16 of the 19 genes with sufficient information for robust ascertainment (Binomial test, P &amp;lt; 0.005, 2-tailed). Conclusions and implications These results support the kinship theory of imprinting and indicate that future studies of BAT, and its roles in human health and disease, may usefully focus on effects of imprinted genes and associated genomic conflicts.

In vivo imaging of brown adipose tissue vasculature reactivity during adrenergic stimulation of non-shivering thermogenesis in mice.

Brown adipose tissue (BAT) is a fat tissue specialized in heat production (non-shivering thermogenesis) and used by mammals to defend core body temperature when exposed to cold. Several studies have shown that during non-shivering thermogenesis the increase in BAT oxygen demand is met by a local and specific increase in tissue's blood flow. While the vasculature of BAT has been extensively studied postmortem in rodents using histology, optical and CT imaging techniques, vasculature changes during stimulation of non-shivering thermogenesis have never been directly detected in vivo. Here, by using computed tomography (CT) angiography with gold nanoparticles we investigate, non-invasively, changes in BAT vasculature during adrenergic stimulation of non-shivering thermogenesis by norepinephrine, a vasoconstrictor known to mediate brown fat heat production, and by CL 316,243, a specific β3-adrenergic agonist also known to elicit BAT thermogenesis in rodents. We found that while CL 316,243 causes local vasodilation in BAT, with little impact on the rest of the vasculature throughout the body, norepinephrine leads to local vasodilation in addition to peripheral vasoconstriction. As a result, a significantly greater relative increase in BAT perfusion is observed following the injection of NE compared to CL. This study demonstrates the use of in vivo CT angiography as an effective tool in assessing vascular reactivity in BAT both qualitatively and quantitatively in preclinical studies.

The natural product rotundic acid treats both aging and obesity by inhibiting PTP1B

AbstractThe occurrence of obesity is associated with age. But their interplay remains mysterious. Here, we discovered that rotundic acid (RA), a plant-derived pentacyclic triterpene, was a powerful agent for both anti-aging and treating obesity. Considering that obese individuals decrease the appetite-suppressing and energy-expenditure-enhancing functions of leptin leading to obesity, we found RA was a leptin sensitizer, evidenced by observations that RA enhanced the leptin sensitivity to normal diet-induced obese (DIO) mice, and had minimal or no use to normal lean mice, leptin receptor-deficient (db/db) mice, and leptin-deficient (ob/ob) mice. Simultaneously, RA significantly increased energy expenditure, BAT thermogenesis, and glucose metabolism in DIO mice, as the results of enhancing leptin sensitivity. Regarding mode of action, we demonstrated that RA is a noncompetitive inhibitor of leptin negative regulators protein tyrosine phosphatase 1B (PTP1B) and T-cell PTP through interaction with their C-terminus, thus leading to weight loss through enhancing leptin sensitivity. Besides, we showed that deletion of yPTP1 in yeast completely abolished the lifespan extension effect of RA, celstrol, and withaferin A, while these compounds exhibited PTP1B inhibition activity. Furthermore, PTP1B knockdown extend lifespan in yeast and human cells, indicating PTP1B is an important factor regulating cellular aging.

Modulation of hypothalamic AMPK phosphorylation by olanzapine controls energy balance and body weight

BackgroundSecond-generation antipsychotics (SGAs) are a mainstay therapy for schizophrenia. SGA-treated patients present higher risk for weight gain, dyslipidemia and hyperglycemia. Herein, we evaluated the effects of olanzapine (OLA), widely prescribed SGA, in mice focusing on changes in body weight and energy balance. We further explored OLA effects in protein tyrosine phosphatase-1B deficient (PTP1B-KO) mice, a preclinical model of leptin hypersensitivity protected against obesity. MethodsWild-type (WT) and PTP1B-KO mice were fed an OLA-supplemented diet (5 mg/kg/day, 7 months) or treated with OLA via intraperitoneal (i.p.) injection or by oral gavage (10 mg/kg/day, 8 weeks). Readouts of the crosstalk between hypothalamus and brown or subcutaneous white adipose tissue (BAT and iWAT, respectively) were assessed. The effects of intrahypothalamic administration of OLA with adenoviruses expressing constitutive active AMPKα1 in mice were also analyzed. ResultsBoth WT and PTP1B-KO mice receiving OLA-supplemented diet presented hyperphagia, but weight gain was enhanced only in WT mice. Unexpectedly, all mice receiving OLA via i.p. lost weight without changes in food intake, but with increased energy expenditure (EE). In these mice, reduced hypothalamic AMPK phosphorylation concurred with elevations in UCP-1 and temperature in BAT. These effects were also found by intrahypothalamic OLA injection and were abolished by constitutive activation of AMPK in the hypothalamus. Additionally, OLA i.p. treatment was associated with enhanced Tyrosine Hydroxylase (TH)-positive innervation and less sympathetic neuron-associated macrophages in iWAT. Both central and i.p. OLA injections increased UCP-1 and TH in iWAT, an effect also prevented by hypothalamic AMPK activation. By contrast, in mice fed an OLA-supplemented diet, BAT thermogenesis was only enhanced in those lacking PTP1B. Our results shed light for the first time that a threshold of OLA levels reaching the hypothalamus is required to activate the hypothalamus BAT/iWAT axis and, therefore, avoid weight gain. ConclusionOur results have unraveled an unexpected metabolic rewiring controlled by hypothalamic AMPK that avoids weight gain in male mice treated i.p. with OLA by activating BAT thermogenesis and iWAT browning and a potential benefit of PTP1B inhibition against OLA-induced weight gain upon oral treatment.

HCBP6-induced activation of brown adipose tissue and upregulated of BAT cytokines genes

Brown adipose tissue is a thermogenic organ, which consumes chemical energy as heat to protect animals from low temperature and metabolic diseases. However, the role and mechanism of the new factor that up-regulates the heat-generating capacity of brown adipose tissue is still unclear. Here, we found that hepatitis C virus core binding protein 6 (HCBP6), as a key regulator gene in the homeostasis of liver lipid metabolism, is an important enhancer for activating brown fat to ensure thermogenesis. HCBP6 upregulates the expression of UCP1 and increases the number of mitochondria in brown adipocytes. In the BAT of HCBP6-knockout mice induced by a high-fat diet, UCP1 and BAT activity-related genes Pgc1α, Cidea and oxidation phosphorylation-related genes (OXPHOS) were significantly reduced. In addition, the transcriptomics results show that the loss of HCBP6 caused disorder of the metabolic pathway, the expression of brown adipocyte development genes was significantly reduced, and the expression of most BAT cytokine genes was reduced. In conclusion, HCBP6 increased ucp1-dependent thermogenesis in BAT and improved liver lipid metabolism, possibly by enhancing the activity of brown fat and changing the expression of BAT cytokine genes.