Lipolysis In Brown Adipose Tissue Research Articles

The effects of the β1-adrenergic receptor antagonist bisoprolol administration on mirabegron-stimulated human brown adipose tissue thermogenesis.

Pharmacological stimulation of human brown adipose tissue (BAT) has been hindered by ineffective activation or undesirable off-target effects. Oral administration of the maximal allowable dose of mirabegron (200 mg), a β3-adrenergic receptor (β3-AR) agonist, has been effective in stimulating BAT thermogenesis and whole-body energy expenditure. However, this has been accompanied by undesirable cardiovascular effects. Therefore, we hypothesized that combining mirabegron with a β1-AR antagonist could suppress these unwanted effects and increase the stimulation of the β3-AR and β2-AR in BAT. We performed a randomized crossover trial (NCT04823442) in 8 lean men. Mirabegron (200 mg) was administered orally with or without the β1-AR antagonist bisoprolol (10 mg). Dynamic [11C]-acetate and 2-deoxy-2-[18F]fluoro-d-glucose PET/CT scans were performed sequentially after oral administration of mirabegron ± bisoprolol. Compared to room temperature, mirabegron alone increased BAT oxidative metabolism (0.84 ± 0.46 vs. 1.79 ± 0.91 min-1, p = 0.0433), but not when combined with bisoprolol. The metabolic rate of glucose in BAT, measured using [18F]FDG PET, was significantly higher with mirabegron than mirabegron with bisoprolol (24 ± 10 vs. 16 ± 8 nmol/g/min, p = 0.0284). Bisoprolol inhibited the mirabegron-induced increase in systolic blood pressure and heart rate. The administration of bisoprolol decreases the adverse cardiovascular effects of mirabegron. However, the provided dose also blunted the mirabegron-stimulated increase in BAT lipolysis, thermogenesis, and glucose uptake. The attenuation in BAT blood flow induced by the large dose of bisoprolol may have limited BAT thermogenesis.

Connexin43 in mesenchymal lineage cells regulates body adiposity and energy metabolism in mice.

Connexin43 (Cx43) is the most abundant gap junction protein present in the mesenchymal lineage. In mature adipocytes, Cx43 mediates white adipose tissue (WAT) beiging in response to cold exposure and maintains the mitochondrial integrity of brown adipose tissue (BAT). We found that genetic deletion of Gja1 (Cx43 gene) in cells that give rise to chondro-osteogenic and adipogenic precursors driven by the Dermo1/Twist2 promoter led to lower body adiposity and partial protection against the weight gain and metabolic syndrome induced by a high-fat diet (HFD) in both sexes. These protective effects were related to increased locomotion, fuel utilization, energy expenditure, nonshivering thermogenesis, and better glucose tolerance in conditionally Gja1-ablated mice. Accordingly, Gja1-mutant mice exhibited reduced adipocyte hypertrophy, partially preserved insulin sensitivity, increased BAT lipolysis, and decreased whitening under HFD. This metabolic phenotype was not reproduced with more restricted Gja1 ablation in differentiated adipocytes, suggesting that Cx43 in adipocyte progenitors or other targeted cells restrains energy expenditures and promotes fat accumulation. These results reveal what we believe is a hitherto unknown action of Cx43 in adiposity, and offer a promising new pharmacologic target for improving metabolic balance in diabetes and obesity.

Exosomal EIF5A derived from Lewis lung carcinoma induced adipocyte wasting in cancer cachexia

Cancer cachexia is a systemic inflammation-driven syndrome, characterized by muscle atrophy and adipose tissue wasting, with progressive weight loss leading to serious impairment of physiological function. Extracellular vesicles (EVs) derived from cancer cells play a significant role in adipocyte lipolysis, yet the mechanism remain uneclucidated. In this study, EVs derived from Lewis lung carcinoma (LLC) cells were extracted and characterized. 3T3-L1 and HIB1B adipocytes were cultured with conditioned medium or EVs from LLC, and LLC cells were used to establish a cancer cachexia mouse model. EVs derived from LLC cells were taken up by 3T3-L1 and HIB1B adipocytes, and derived exosomal EIF5A protein-induced lipolysis of adipocytes. High level of EIF5A was expressed in EVs from LLC cells, exosomal EIF5A is linked to lipid metabolism. Elevated expression of EIF5A is associated with shorter overall survival in lung cancer patients. Western blots, glycerol release and Oil red O staining assays were used to evaluate lipolysis of adipocytes. The reduction of lipolysis in 3T3-L1 and HIB1B adipocytes is achieved through silencing EIF5A or treating with pharmacologic inhibitor GC7 in vitro, and suppressing the expression of EIF5A in LLC cells by infected with shRNA or GC7 treatment partly alleviated white and brown adipose tissue lipolysis in vivo. Mechanistically, EIF5A directly binds with G protein-coupled bile acid receptor 1 (GPBAR1) mRNA to promote its translation and then activates cAMP response element binding protein (CREB) signaling pathway to induce lipolysis. This study demonstrates that exosomal EIF5A from LLC cells, with hypusinated EIF5A, has a lipolytic effect on adipocyte and adipose tissues in cancer cachexia model. Exosomal EIF5A could be involved in lipolysis and these findings indicate that a novel regulator and potential target for cachexia treatment.

80-OR: A New Cytoskeleton-Based Mechanism for Regulating Brown Adipose Tissue Physiology

Human genetic variants in ANK2, encoding the scaffold protein ankyrin-B (AnkB), increase risk for T2D. We characterized the role of AnkB in white adipose tissue (WAT) in mice with AnkB deficiency in both WAT and brown adipose tissue (BAT) (AT-AnkB KO). We found that AnkB loss led to obesity and insulin resistance driven by its role in clathrin mediated endocytosis of GLUT4 in WAT. AT-AnkB KO mice also had lipid accumulation in BAT. However, the cell-autonomous roles of AnkB in BAT and its contribution to energy balance is unknown. To elucidate AnkB’s roles in BAT, we developed mice lacking AnkB in BAT (BAT-AnkB KO). Histology and TEM revealed lipid accumulation in BAT of 4-month-old BAT-AnkB KO mice housed at thermoneutrality. Consistent with this finding, brown adipocytes from AnkB deficient mice also have enlarged lipid droplets, suggesting an AnkB cell-autonomous role in BAT lipid homeostasis. Proteomic-MS revealed that AnkB forms complexes with lipolysis factors Atgl, Hsl and Plin1, and regulators of the PKA pathway, suggesting AnkB plays a role regulating BAT lipolysis. Interestingly, Hsl and Plin1 are elevated in BAT despite the enlarged LDs of BAT-AnkB KO mice, implying either lipolytic deficits or compensatory effects. These findings support RNA sequencing that revealed downregulation of PKA signaling genes, ATPase subunits, and mitochondrial calcium signaling genes in BAT of BAT-AnkB KO mice. Last, peri-droplet mitochondria (PDM), a mitochondria subpopulation with reduced beta-oxidation capacity that contacts LDs, form longer contact sites with BAT LDs from BAT-AnkB KO mice. Together, these findings suggest that early alterations in mitochondrial bioenergetics and lipolysis contribute to BAT LD accumulation. Along with this data, we will present findings on thermogenic regulation in vivo and physiological assays evaluating lipolysis and its major regulators. Disclosure A.Aguillard: None. J.Arricastres: None. J.Tzeng: None. D.Lorenzo: None. Funding American Diabetes Association (1-19-JDF-081 to D.L.); National Science Foundation; Burroughs Wellcome Fund (1022069)

Creatine ameliorates high-fat diet-induced obesity by regulation of lipolysis and lipophagy in brown adipose tissue and liver

Diet-induced obesity in mice and humans is commonly associated with an imbalance between energy intake and expenditure. Reportedly, creatine can enhance energy expenditure in brown adipose tissue and reduce hepatic triglycerides accumulation; however, the molecular mechanism underlying the role of exogenous creatine supplementation in regulating lipid droplet mobilization remains elusive. Herein, we employed a high-fat diet (HFD)- induced mouse model to investigate the role of creatine in regulating lipolysis and lipophagy in brown adipose tissue and the liver. Exogenous creatine supplementation ameliorated HFD-induced obesity, increased insulin sensitivity and improved glucose homeostasis. Creatine supplementation enhanced the expression of uncoupling protein 1 (UCP1), cell death-inducing DNA fragmentation factor alpha-like effector A (CIDEA), and other brown adipose tissue-specific thermogenic genes Cpt1a, Gyk, and Pgc1β in brown adipose tissue. Furthermore, creatine inhibited the expression of CIDEA, which promotes hepatic lipid accumulation. Creatine stimulated the expression of triglyceride lipase adipose triglyceride lipase, and phospho-hormone-sensitive lipase (HSL) induced increased lipolysis in brown adipose tissue and the liver. Meanwhile, reduced LC3B expression was accompanied by an increased level of p62 in HFD-fed mice, indicating diminished basal autophagy in brown adipose tissue and the liver; however, creatine enhanced P62/LC3B induced lipophagy in brown adipose tissue and the liver. Collectively, our results suggest that creatine may function as a brown adipose tissue activator to increase whole-body energy metabolism via coordinated lipolysis and lipophagy in brown adipose tissue and the liver.

Abstract 2091: Living in the cold without brown adipose tissue lipolysis

Abstract 2091: Living in the cold without brown adipose tissue lipolysis

Overexpressing the hydroxycarboxylic acid receptor 1 in mouse brown adipose tissue restores glucose tolerance and insulin sensitivity in diet-induced obese mice.

Interscapular brown adipose tissue (BAT) plays an important role in controlling glucose homeostasis. Increased glucose entry and glycolysis in BAT result in lactate production and release. The adipose tissue expresses the lactate receptor hydrocarboxylic acid receptor 1 (HCAR1), markedly downregulated in male diet-induced obese (DIO) and ob/ob mice. In this study, we examined the role of HCAR1 in BAT in controlling glucose homeostasis in male DIO mice. We overexpressed HCAR1 in BAT by injecting adeno-associated viruses (AAVs) expressing HCAR1 into the BAT pads of male DIO C57BL/6J mice. Overexpressing HCAR1 in BAT resulted in augmented glucose uptake by BAT in response to treatment with the HCAR1 agonist. HCAR1 overexpression elevated BAT temperature associated with increased thermogenic gene expression in BAT. HCAR1 overexpression prevented body weight gain in male DIO mice. Importantly, mice overexpressing HCAR1 in BAT exhibited improved glucose tolerance and insulin sensitivity. HCAR1 overexpression upregulated the Slc2a4 gene expression and promoted GLUT4 trafficking to the plasma membrane. In addition, mice overexpressing HCAR1 displayed a decrease in hormone-sensitive lipase (HSL) phosphorylation and increased lipogenic enzyme gene expression in BAT. Unlike DIO mice, overexpressing HCAR1 in BAT of mice fed a low-fat diet did not change body weight gain and glucose homeostasis. Taken together, our results support the interpretation that HCAR1 expressed in BAT promotes glucose entry and reduces lipolysis in BAT of male DIO mice. As activation of HCAR1 in BAT restores body weight, glucose tolerance, and insulin sensitivity in male DIO mice, our study suggests that interoceptive lactate detection via HCAR1 in BAT can regulate glucose and lipid substrate utilization and/or availability to promote healthy metabolism.NEW & NOTEWORTHY HCAR1 expressed in BAT can promote glucose entry and reduce lipolysis, resulting in body weight loss and increased insulin sensitivity. Hence, targeting HCAR1 in BAT would provide an alternative way to control body weight and euglycemia in individuals with obesity.

Brown adipose tissue involution associated with progressive restriction in progenitor competence.

Human brown adipose tissue (BAT) undergoes progressive involution. This involution process is not recapitulated in rodents, and the underlying mechanisms are poorly understood. Here we show that the interscapular BAT (iBAT) of rabbits whitens rapidly during early adulthood. The transcriptomic remodeling and identity switch of mature adipocytes are accompanied by loss of brown adipogenic competence of progenitors. Single-cell RNA sequencing reveals that rabbit and human iBAT progenitors highly express the FSTL1 gene. When iBAT involutes in rabbits, adipocyte progenitors reduce FSTL1 expression and are refractory to brown adipogenic recruitment. Conversely, FSTL1 is constitutively expressed in mouse iBAT to sustain WNT signaling and prevent involution. Progenitor incompetence and iBAT paucity can be induced in mice by genetic deletion of the Fstl1 gene or ablation of Fstl1+ progenitors. Our results highlight the hierarchy and dynamics of the BAT progenitor compartment and implicate the functional incompetence of FSTL1-expressing progenitors in BAT involution.

Genomic and Non-Genomic Actions of Glucocorticoids on Adipose Tissue Lipid Metabolism.

Glucocorticoids (GCs) are hormones that aid the body under stress by regulating glucose and free fatty acids. GCs maintain energy homeostasis in multiple tissues, including those in the liver and skeletal muscle, white adipose tissue (WAT), and brown adipose tissue (BAT). WAT stores energy as triglycerides, while BAT uses fatty acids for heat generation. The multiple genomic and non-genomic pathways in GC signaling vary with exposure duration, location (adipose tissue depot), and species. Genomic effects occur directly through the cytosolic GC receptor (GR), regulating the expression of proteins related to lipid metabolism, such as ATGL and HSL. Non-genomic effects act through mechanisms often independent of the cytosolic GR and happen shortly after GC exposure. Studying the effects of GCs on adipose tissue breakdown and generation (lipolysis and adipogenesis) leads to insights for treatment of adipose-related diseases, such as obesity, coronary disease, and cancer, but has led to controversy among researchers, largely due to the complexity of the process. This paper reviews the recent literature on the genomic and non-genomic effects of GCs on WAT and BAT lipolysis and proposes research to address the many gaps in knowledge related to GC activity and its effects on disease.

β3-Adrenergic receptors regulate human brown/beige adipocyte lipolysis and thermogenesis.

β3-Adrenergic receptors (β3-ARs) are the predominant regulators of rodent brown adipose tissue (BAT) thermogenesis. However, in humans, the physiological relevance of BAT and β3-AR remains controversial. Herein, using primary human adipocytes from supraclavicular neck fat and immortalized brown/beige adipocytes from deep neck fat from 2 subjects, we demonstrate that the β3-AR plays a critical role in regulating lipolysis, glycolysis, and thermogenesis. Silencing of the β3-AR compromised genes essential for thermogenesis, fatty acid metabolism, and mitochondrial mass. Functionally, reduction of β3-AR lowered agonist-mediated increases in intracellular cAMP, lipolysis, and lipolysis-activated, uncoupling protein 1–mediated thermogenic capacity. Furthermore, mirabegron, a selective human β3-AR agonist, stimulated BAT lipolysis and thermogenesis, and both processes were lost after silencing β3-AR expression. This study highlights that β3-ARs in human brown/beige adipocytes are required to maintain multiple components of the lipolytic and thermogenic cellular machinery and that β3-AR agonists could be used to achieve metabolic benefit in humans.

Human Brown Adipocyte Thermogenesis Is Driven by β2-AR Stimulation

Stimulation of brown adipose tissue (BAT) thermogenesis in humans has emerged as an attractive target to improve metabolic health. Pharmacological stimulations targeting the β3-adrenergic receptor (β3-AR), the adrenergic receptor believed to mediate BAT thermogenesis, have historically performed poorly in human clinical trials. Here we report that, in contrast to rodents, human BAT thermogenesis is not mediated by the stimulation of β3-AR. Oral administration of the β3-AR agonist mirabegron only elicited increases in BAT thermogenesis when ingested at the maximal allowable dose. This led to off-target binding to β1-AR and β2-AR, thereby increasing cardiovascular responses and white adipose tissue lipolysis, respectively. ADRB2 was co-expressed with UCP1 in human brown adipocytes. Pharmacological stimulation and inhibition of the β2-AR as well as knockdown of ADRB1, ADRB2, or ADRB3 in human brown adipocytes all confirmed that BAT lipolysis and thermogenesis occur through β2-AR signaling in humans (ClinicalTrials.govNCT02811289).

2020-P: ß3-Adrenergic Receptors Regulate Lipolysis and Thermogenesis in Human Brown/Beige Adipocytes

Activation of rodent brown adipose tissue (BAT) via pharmacological stimulation of β3-adrenergic receptors (β3-AR) leads to metabolic benefit, however in humans, the physiological relevance of BAT and β3-AR remain controversial. To investigate the role of the β3-AR in human brown adipocytes, first, we established a human primary supraclavicular adipocyte in vitro model that upon differentiation preserved the physiological properties brown adipose tissue with increased β-ARs, adipogenic, thermogenic and brown/beige markers. Next, we selective silenced β3-AR expression in differentiated primary brown/beige adipocytes using a lipofectamine-based non-viral transfection. 48h of transfection of siRNA targeting ADRB3 (siRNA-ADRB3) resulted in a 90% reduction in ADRB3 mRNA levels, relative to control siRNA-transfected cells (siRNA-Ctrl). siRNA-ADRB3 also reduced genes of fatty acid metabolism, thermogenesis (UCP1, 90% decrease), and mitochondrial mass. Functionally, lower cAMP levels, lipolysis, oxygen consumption rates and higher glycolysis were caused by silencing β3-AR receptor. Immortalized brown adipocyte (hBA’s), from a separate subject, displayed a similar decrease in lipolysis and cellular respiration. Mirabegron, the selective human β3-AR agonist, stimulated BAT lipolysis and thermogenesis, that were lost after knockdown ADRB3. Similarly, selective subtype human β-AR agonists dobutamine (β1-AR agonist) and terbutaline (β2-AR agonist) treatment also increased lipolysis and thermogenesis, that were also attenuated when β3-AR was silenced. Thus, the β3-AR maintains multiple components of the human brown/beige adipocyte lipolytic and thermogenic cellular machinery. These findings indicate that ADRB3 and β3-AR agonists could be used to achieve metabolic benefit in humans. Disclosure C. Cero: None. H.J. Lea: None. K.Y. Zhu: None. A.M. Cypess: None.

Sinapic acid induces the expression of thermogenic signature genes and lipolysis through activation of PKA/CREB signaling in brown adipocytes

Lipid accumulation in white adipose tissue is the key contributor to the obesity and orchestrates numerous metabolic health problems such as type 2 diabetes, hypertension, atherosclerosis, and cancer. Nonetheless, the prevention and treatment of obesity are still inadequate. Recently, scientists found that brown adipose tissue (BAT) in adult humans has functions that are diametrically opposite to those of white adipose tissue and that BAT holds promise for a new strategy to counteract obesity. In this study, we evaluated the potential of sinapic acid (SA) to promote the thermogenic program and lipolysis in BAT. SA treatment of brown adipocytes induced the expression of brown-adipocyte activation–related genes such as Ucp1, Pgc-1α, and Prdm16. Furthermore, structural analysis and western blot revealed that SA upregulates protein kinase A (PKA) phosphorylation with competitive inhibition by a pan-PKA inhibitor, H89. SA binds to the adenosine triphosphate (ATP) site on the PKA catalytic subunit where H89 binds specifically. PKA-cat-α1 gene–silencing experiments confirmed that SA activates the thermogenic program via a mechanism involving PKA and cyclic AMP response element–binding protein (CREB) signaling. Moreover, SA treatment promoted lipolysis via a PKA/p38-mediated pathway. Our findings may allow us to open a new avenue of strategies against obesity and need further investigation.

Human BAT Thermogenesis is Stimulated by the β <sub>2</sub>-Adrenergic Receptor

Stimulation of brown adipose tissue (BAT) thermogenesis in humans has emerged as an attractive target to improve metabolic health. Pharmacological stimulations targeting the β3-adrenergic receptor (β3-AR), the adrenergic receptor believed to mediate BAT thermogenesis, have historically performed poorly in human clinical trials. Here we report that, in contrast to rodents, human BAT thermogenesis is not mediated by the stimulation of the β3-AR but rather driven primarily through the β2-AR. Oral administration of the β3-AR agonist mirabegron only elicited increases in BAT thermogenesis when ingested at the maximal allowable dose. Such a dose led to off-target binding to the β1-AR and β2-AR, thereby increasing cardiovascular responses and white adipose tissue lipolysis, respectively. In vitro pharmacological stimulation as well as pharmacological and genetic inhibition of the β2-AR in human primary brown adipocytes all confirmed that this β-AR subtype is essential to simulate BAT lipolysis and thermogenesis in humans (ClinicalTrials.gov NCT02811289).

Ucp1 and metabolism-related gene expression response to high fat diets in brown adipose tissue of TALLYHO/JngJ vs. C57BL/6J mice

In the midst of the ongoing obesity epidemic, brown adipose tissue (BAT) has emerged as a potential therapeutic target. BAT is a thermogenic organ in mammals that is characterized by adipocytes with numerous mitochondria. BAT uses cellular free fatty acids derived from the lipolysis of triglyceride droplets to generate heat via the action of uncoupling protein 1 (Ucp1), located in the inner mitochondrial membrane. In this study, we analyzed mRNA and protein levels of Ucp1 and genes related to inflammation, mitochondrial biogenesis, and lipolysis in BAT of the TALLYHO/JngJ (TH) mouse, a polygenic model of obesity and type 2 diabetes. At four weeks of age, TH and C57BL/6J (B6) mice were weaned onto chow or high fat (HF) diets. At twenty weeks of age, mice were killed, and interscapular BAT was collected. BAT of TH mice appeared discolored and larger than that of B6. mRNA and protein levels in BAT were measured using qPCR and western blot analysis, respectively. There were no significant differences in Ucp1 mRNA levels between TH and B6 mice on either diet. Inflammatory marker interleukin 6 (IL6) mRNA levels were significantly increased in TH mice on HF diets compared to other groups. Interestingly, HF diets increased adipose triglyceride lipase (ATGL) mRNA levels in B6 mice, but not in TH. In summary, we observed genotype-dependent responses to HF diets for IL6 and ATGL expressions in BAT of TH and B6 mice. These results may signify increased inflammation and reduced lipolysis in BAT during the development of obesity.

Prolonged inorganic arsenic exposure via drinking water impairs brown adipose tissue function in mice

Although epidemiologic studies show an association between long-term environmental inorganic arsenic (iAs) exposure and various disorders of glucose and lipid metabolism, the mechanisms of these ailments remain unclear. While white adipose tissue (WAT) essentially acts as a storage tissue for energy and is key to energy homeostasis, brown adipose tissue (BAT) consumes excess energy via uncoupling protein 1-mediated non-shivering thermogenesis in mitochondria and helps maintain the steady state of glucose and lipid metabolism. Our previous in vitro work found that iAs may inhibit adipogenesis and glucose uptake in adipocytes, leading us to hypothesize that chronic exposure to iAs in vivo may also affect the development and function of BAT, which plays a part in iAs-induced metabolic disorders. Thus, adult C57BL/6J female mice were provided drinking water containing 5 or 20 ppm of inorganic arsenicals (iAs3+ and iAs5+) for 17 weeks and control mice were given unaltered water. In these mice, iAs exposure induced cold intolerance and lipid accretion in BAT. In addition, iAs exposure impaired expression of various genes related to thermogenesis, mitochondrial function, adipocyte differentiation, as well as lipolysis in BAT of the exposed mice. These findings suggest a novel toxicity of iAs in BAT occurring via induction of BAT malfunction and impairment of thermogenesis. This novel toxicological linkage helps explain the mechanisms linking iAs exposure to increased risk of disorders of glucose and lipid metabolism.

Increased FGF21 in brown adipose tissue of tyrosine hydroxylase heterozygous mice: implications for cold adaptation

Tyrosine hydroxylase (TH) catalyzes the first step in catecholamines synthesis. We studied the impact of reduced TH in brown adipose tissue (BAT) activation. In adult heterozygous (Th+/- ) mice, dopamine and noradrenaline (NA) content in BAT decreased after cold exposure. This reduced catecholaminergic response did not impair cold adaptation, because these mice induced uncoupling protein 1 (UCP-1) and maintained BAT temperature to a similar extent than controls (Th+/+ ). Possible compensatory mechanisms implicated were studied. Prdm16 and Fgf21 expression, key genes in BAT activation, were elevated in Th+/- mice at thermoneutrality from day 18.5 of embryonic life. Likewise, plasma FGF21 and liver Fgf21 mRNA were increased. Analysis of endoplasmic reticulum (ER) stress, a process that triggers elevations in FGF21, showed higher phospho-IRE1, phospho-JNK, and CHOP in BAT of Th+/- mice at thermoneutrality. Also, increased lipolysis in BAT of cold-exposure Th+/- mice was demonstrated by increased phosphorylation of hormone-sensitive lipase (HSL), as well as diacylglycerol (DAG) and FFA content. Overall, these results indicate that the mild effects of Th haploinsufficiency on BAT function are likely due to compensatory mechanisms involving elevations in Fgf21 and Prdm16 and through adaptive changes in the lipid profile.

Administration of Thyrotropin-Releasing Hormone in the Hypothalamic Paraventricular Nucleus of Male Rats Mimics the Metabolic Cold Defense Response

Background: Cold exposure increases thyrotropin-releasing hormone (TRH) expression primarily in the hypothalamic paraventricular nucleus (PVN). The PVN is a well-known hypothalamic hub in the control of energy metabolism. TRH terminals and receptors are found on PVN neurons. We hypothesized that TRH release in the PVN plays an important role in the control of thermogenesis and energy mobilization during cold exposure. Methods: Male Wistar rats were exposed to a cold environment (4°C) or TRH retrodialysis in the PVN for 2 h. We compared the effects of cold exposure and TRH administration in the PVN on plasma glucose, corticosterone, and thyroid hormone concentrations, body temperature, locomotor activity, as well as metabolic gene expression in the liver and brown adipose tissue. Results: Cold exposure increased body temperature, locomotor activity, and plasma corticosterone concentrations, but blood glucose concentrations were similar to that of room temperature control animals. TRH administration in the PVN also promptly increased body temperature, locomotor activity and plasma corticosterone concentrations. However, TRH administration in the PVN markedly increased blood glucose concentrations and endogenous glucose production (EGP) compared to saline controls. Selective hepatic sympathetic or parasympathetic denervation reduced the TRH-induced increase in glucose concentrations and EGP. Gene expression data indicated increased gluconeogenesis in liver and lipolysis in brown adipose tissue, both after cold exposure and TRH administration. Conclusions: We conclude that TRH administration in the rat PVN largely mimics the metabolic and behavioral changes induced by cold exposure indicating a potential link between TRH release in the PVN and cold defense.

Deficiency of the basic helix-loop-helix transcription factor DEC1 prevents obesity induced by a high-fat diet in mice.

Obesity is a major public health problem in developed countries resulting from increased food intake and decreased energy consumption and usually associated with abnormal lipid metabolism. Here, we show that DEC1, a basic helix-loop-helix transcription factor, plays an important role in the regulation of lipid consumption in mouse brown adipose tissue (BAT), which is the major site of thermogenesis. Homozygous Dec1 deletion attenuated high-fat-diet-induced obesity, adipocyte hypertrophy, fat volume and hepatic steatosis. Furthermore, DEC1 deficiency increased body temperature during daytime and enhanced the expression of uncoupler protein 1, a key factor of thermogenesis, and various lipolysis-related genes in interscapular BAT. In vitro experiments suggested that DEC1 suppresses the expression of various lipolysis-related genes induced by the heterodimer of peroxisome proliferator-activated receptor γ and retinoid X receptor α (RXRα) through direct binding to RXRα. These observations suggest that enhanced lipolysis in BAT caused by DEC1 deficiency leads to an increase in lipid consumption, thereby decreasing lipid accumulation in adipose tissues and the liver. Thus, DEC1 may serve as an energy-saving factor that suppresses lipid consumption, which may be relevant to managing obesity.

Brown adipose tissue and lipid metabolism

This article explores how the interplay between lipid metabolism and thermogenic adipose tissues enables proper physiological adaptation to cold environments in rodents and humans. Cold exposure triggers systemic changes in lipid metabolism, which increases fatty acid delivery to brown adipose tissue (BAT) by various routes. Next to fatty acids generated intracellularly by de-novo lipogenesis or by lipolysis at lipid droplets, brown adipocytes utilize fatty acids released by white adipose tissue (WAT) for adaptive thermogenesis. WAT-derived fatty acids are internalized directly by BAT, or indirectly after hepatic conversion to very low-density lipoproteins and acylcarnitines. In the postprandial state, chylomicrons hydrolyzed by lipoprotein lipase - activated specifically in thermogenic adipocytes - are the predominant fatty acid source. Cholesterol-enriched chylomicron remnants and HDL generated by intravascular lipolysis in BAT are cleared more rapidly by the liver, explaining the antiatherogenic effects of BAT activation. Notably, increased cholesterol flux and elevated hepatic synthesis of bile acids under cold exposure further promote BAT-dependent thermogenesis. Although pathways providing fatty acids for activated BAT have been identified, more research is needed to understand the integration of lipid metabolism in BAT, WAT and liver, and to determine the relevance of BAT for human energy metabolism.