Query: UCP1

title: New Advances in Adaptive Thermogenesis: UCP1 and Beyond.
abstract: Brown and beige adipocytes can catabolize stored energy to generate heat, and this distinct capacity for thermogenesis could be leveraged as a therapy for metabolic diseases like obesity and type 2 diabetes. Thermogenic adipocytes drive heat production through close coordination of substrate supply with the mitochondrial oxidative machinery and effectors that control the rate of substrate oxidation. Together, this apparatus affords these adipocytes with tremendous capacity to drive thermogenesis. The best characterized thermogenic effector is uncoupling protein 1 (UCP1) Importantly, additional mechanisms for activating thermogenesis beyond UCP1 have been identified and characterized to varying extents. Acute regulation of these thermogenic pathways has been an active area of study, and numerous regulatory factors have been uncovered in recent years. Here we will review the evidence for regulators of heat production in thermogenic adipocytes in the context of the thermodynamic and kinetic principles that govern their therapeutic utility.

title: UCP1 independent thermogenesis.
abstract: Obesity results from energy imbalance, when energy intake exceeds energy expenditure. Brown adipose tissue (BAT) drives non shivering thermogenesis which represents a powerful mechanism of enhancing the energy expenditure side of the energy balance equation. The best understood thermogenic system in BAT that evolved to protect the body from hypothermia is based on the uncoupling of protonmotive force from oxidative phosphorylation through the actions of uncoupling protein 1 (UCP1) a key regulator of cold mediated thermogenesis. Similarly, energy expenditure is triggered in response to caloric excess, and animals with reduced thermogenic fat function can succumb to diet induced obesity. Thus, it was surprising when inactivation of Ucp1 did not potentiate diet induced obesity. In recent years, it has become clear that multiple thermogenic mechanisms exist, based on ATP sinks centered on creatine, lipid, or calcium cycling, along with Fatty acid mediated UCP1 independent leak pathways driven by the ADP/ATP carrier (AAC) With a key difference between cold and diet induced thermogenesis being the dynamic changes in purine nucleotide (primarily ATP) levels, ATP dependent thermogenic pathways may play a key role in diet induced thermogenesis. Additionally, the ubiquitous expression of AAC may facilitate increased energy expenditure in many cell types, in the face of over feeding. Interest in UCP1 independent energy expenditure has begun to showcase the therapeutic potential that lies in refining our understanding of the diversity of biochemical pathways controlling thermogenic respiration.

title: FGF6 and FGF9 regulate UCP1 expression independent of brown adipogenesis
abstract: Uncoupling protein 1 (UCP1) plays a central role in energy dissipation in brown adipose tissue (BAT) Using high throughput library screening of secreted peptides, we identify two fibroblast growth factors (FGF) FGF6 and FGF9, as potent inducers of UCP1 expression in adipocytes and preadipocytes. Surprisingly, this occurs through a mechanism independent of adipogenesis and involves FGF receptor 3 (FGFR3) prostaglandin E2 and interaction between estrogen receptor related alpha, flightless 1 (FLII) and leucine rich repeat (in FLII) interacting protein 1 as a regulatory complex for UCP1 transcription. Physiologically, FGF6/9 expression in adipose is upregulated by exercise and cold in mice, and FGF9/FGFR3 expression in human neck fat is significantly associated with UCP1 expression. Loss of FGF9 impairs BAT thermogenesis. In vivo administration of FGF9 increases UCP1 expression and thermogenic capacity. Thus, FGF6 and FGF9 are adipokines that can regulate UCP1 through a transcriptional network that is dissociated from brown adipogenesis, and act to modulate systemic energy metabolism. Uncoupling protein 1 (UCP1) plays a central role in energy dissipation in brown adipose tissue. Here the authors show that FGF6 and FGF9 induce UCP1 expression in adipocytes and preadipocytes, via modulation of a transcriptional network that is dissociated from brown adipogenesis.

title: Endogenous FGF21 signaling controls paradoxical obesity resistance of UCP1 deficient mice
abstract: Uncoupling protein 1 (UCP1) executes thermogenesis in brown adipose tissue, which is a major focus of human obesity research. Although the UCP1 knockout (UCP1 KO) mouse represents the most frequently applied animal model to judge the anti obesity effects of UCP1, the assessment is confounded by unknown anti obesity factors causing paradoxical obesity resistance below thermoneutral temperatures. Here we identify the enigmatic factor as endogenous FGF21, which is primarily mediating obesity resistance. The generation of UCP1/FGF21 double knockout mice (dKO) fully reverses obesity resistance. Within mild differences in energy metabolism, urine metabolomics uncover increased secretion of acyl carnitines in UCP1 KOs, suggesting metabolic reprogramming. Strikingly, transcriptomics of metabolically important organs reveal enhanced lipid and oxidative metabolism in specifically white adipose tissue that is fully reversed in dKO mice. Collectively, this study characterizes the effects of endogenous FGF21 that acts as master regulator to protect from diet induced obesity in the absence of UCP1. Brown adipose thermogenesis increases energy expenditure and relies on uncoupling protein 1 (UCP1) however, UCP1 knock out mice show resistance to diet induced obesity at room temperature. Here, the authors show that this resistance relies on FGF21 signaling, inducing the browning of white adipose tissue.

title: Regulation of UCP1 and Mitochondrial Metabolism in Brown Adipose Tissue by Reversible Succinylation.
abstract: Brown adipose tissue (BAT) is rich in mitochondria and plays important roles in energy expenditure, thermogenesis, and glucose homeostasis. We find that levels of mitochondrial protein succinylation and malonylation are high in BAT and subject to physiological and genetic regulation. BAT specific deletion of Sirt5, a mitochondrial desuccinylase and demalonylase, results in dramatic increases in global protein succinylation and malonylation. Mass spectrometry based quantification of succinylation reveals that Sirt5 regulates the key thermogenic protein in BAT, UCP1. Mutation of the two succinylated lysines in UCP1 to acyl mimetic glutamine and glutamic acid significantly decreases its stability and activity. The reduced function of UCP1 and other proteins in Sirt5KO BAT results in impaired mitochondria respiration, defective mitophagy, and metabolic inflexibility. Thus, succinylation of UCP1 and other mitochondrial proteins plays an important role in BAT and in regulation of energy homeostasis.

title: Depot specific UCP1 expression in human white adipose tissue and its association with obesity related markers
abstract: This study investigated depot specific mRNA expression of uncoupling protein 1 (UCP1) in human white adipose tissue (WAT) and its association with obesity related markers. We recruited 39 normal weight, 41 nondiabetic obese, and 22 diabetic obese women. We measured UCP1 mRNA expression in abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) and investigated the associations between UCP1 mRNA expression in VAT and SAT, and obesity related markers including mRNA expression of leptin, adiponectin, CCAAT enhancer binding protein homologous protein (CHOP) and positive regulatory domain containing protein 16 (PRDM16) We also evaluated UCP1 mRNA expression in differentiated human white adipocytes after treatment with various stressors and metabolic improvement agents in vitro. UCP1 mRNA in VAT was significantly higher than in SAT in all groups. UCP1 mRNA in SAT was negatively correlated with BMI, total abdominal fat area, visceral fat area, blood pressure, fasting glucose, insulin, HOMA IR score, triglyceride, hsCRP, fasting leptin levels, and adipocyte size. UCP1 mRNA in SAT was positively correlated with fasting adiponectin levels. UCP1 mRNA in VAT was negatively correlated with visceral to subcutaneous fat ratio (VSR) fasting glucose, and triglyceride levels. In SAT, UCP1 mRNA was negatively correlated with mRNA expression of leptin and CHOP, and positively correlated with mRNA expression of adiponectin. The expression of PRDM16 was positively correlated with UCP1 mRNA in both VAT and SAT. UCP1 mRNA expression in differentiated human white adipocytes was significantly reduced after incubation with thapsigargin, tunicamycin, homocysteine, TNF a, or IL b, and significantly increased after incubation with exendin 4, dapagliflozin, and telmisartan. This study demonstrated depot specific mRNA expression of UCP1 and its association with obesity related markers in human WAT. UCP1 mRNA in human white adipocytes was suppressed by inflammatory agents and enhanced by metabolic improvement agents. UCP1 in human WAT might participate in the pathogenesis of obesity related metabolic diseases.

title: Melatonin/PGC1A/UCP1 promotes tumor slimming and represses tumor progression by initiating autophagy and lipid browning
abstract: Metabolic adaptations are emerging hallmarks of cancer progression and cellular transformation. Clear cell renal cell carcinoma (ccRCC) is a metabolic disease defined histologically by lipid accumulation and lipid storage, which promote tumor cell survival; however, the significance of eliminating the lipid remains unclear. Here, we demonstrate that melatonin activates transcriptional coactivator peroxisome proliferator activated receptor gamma coactivator 1A (PGC1A) and uncoupling protein 1 (UCP1) dependent lipid autophagy and a lipid browning program to elicit a catabolic state called "tumor slimming," thus suppressing tumor progression. Metabolic coregulator data analysis revealed that PGC1A expression was decreased in ccRCC tissues versus normal tissues, and poor patient outcome was associated with lower expression of PGC1A in The Cancer Genome Atlas (TCGA KIRC) PGC1A was downregulated in ccRCC and associated with disease progression. Restoration of PGC1A expression by melatonin in ccRCC cells significantly repressed tumor progression and eliminated the abnormal lipid deposits. Furthermore, a phenomenon called "tumor slimming" was observed, in which tumor cell volume was reduced and lipid droplets transformed into tiny pieces. Additional studies indicated that melatonin promoted "tumor slimming" and suppressed ccRCC progression through PGC1A/UCP1 mediated autophagy and lipid browning. During this process, autophagy and lipid browning eliminate lipid deposits without providing energy. These studies demonstrate that the novel "tumor slimming" pathway mediated by melatonin/PGC1A/UCP1 exhibits prognostic potential in ccRCC, thus revealing the significance of monitoring and manipulating this pathway for cancer therapy.

title: Ginsenoside Rg1 promotes browning by inducing UCP1 expression and mitochondrial activity in 3T3 L1 and subcutaneous white adipocytes
abstract: Panax ginseng Meyer is known as a conventional herbal medicine, and ginsenoside Rg1, a steroid glycoside, is one of its components. Although Rg1 has been proved to have an antiobesity effect, the mechanism of this effect and whether it involves adipose browning have not been elucidated.  L1 and subcutaneous white adipocytes from mice were used to access the thermogenic effect of Rg1. Adipose mitochondria and uncoupling protein 1 (UCP1) expression were analyzed by immunofluorescence. Protein level and mRNA of UCP1 were also evaluated by Western blotting and real time polymerase chain reaction, respectively. Results Rg1 dramatically enhanced expression of brown adipocyte specific markers, such as UCP1 and fatty acid oxidation genes, including carnitine palmitoyltransferase 1. In addition, it modulated lipid metabolism, activated 5' adenosine monophosphate (AMP) activated protein kinase, and promoted lipid droplet dispersion. Conclusions Rg1 increases UCP1 expression and mitochondrial biogenesis in 3T3 L1 and subcutaneous white adipose cells isolated from C57BL/6 mice. We suggest that Rg1 exerts its antiobesity effects by promoting adipocyte browning through activation of the AMP activated protein kinase pathway.

title: UCP1 independent signaling involving SERCA2b mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis
abstract: Uncoupling protein 1 (UCP1) plays a central role in nonshivering thermogenesis in brown fat; however, its role in beige fat remains unclear. Here we report a robust UCP1 independent thermogenic mechanism in beige fat that involves enhanced ATP dependent Ca2+ cycling by sarco/endoplasmic reticulum Ca2+ ATPase 2b (SERCA2b) and ryanodine receptor 2 (RyR2) Inhibition of SERCA2b impairs UCP1 independent beige fat thermogenesis in humans and mice as well as in pigs, a species that lacks a functional UCP1 protein. Conversely, enhanced Ca2+ cycling by activation of a1 and/or b3 adrenergic receptors or the SERCA2b RyR2 pathway stimulates UCP1 independent thermogenesis in beige adipocytes. In the absence of UCP1, beige fat dynamically expends glucose through enhanced glycolysis, tricarboxylic acid metabolism and pyruvate dehydrogenase activity for ATP dependent thermogenesis through the SERCA2b pathway; beige fat thereby functions as a 'glucose sink' and improves glucose tolerance independently of body weight loss. Our study uncovers a noncanonical thermogenic mechanism through which beige fat controls whole body energy homeostasis via Ca2+ cycling.

title: At thermoneutrality, acute thyroxine induced thermogenesis and pyrexia are independent of UCP1
abstract: Hyperthyroidism is associated with increased metabolism "thyroid thermogenesis" and elevated body temperature, often referred to as hyperthermia. Uncoupling protein 1 (UCP1) is the protein responsible for nonshivering thermogenesis in brown adipose tissue. We here examine whether UCP1 is essential for thyroid thermogenesis.  We investigated the significance of UCP1 for thyroid thermogenesis by using UCP1 ablated (UCP1 KO) mice. To avoid confounding factors from cold induced thermogenesis and to approach human conditions, the experiments were conducted at thermoneutrality, and to resemble conditions of endogenous release, thyroid hormone (thyroxine, T4) was injected peripherally.  Both short term and chronic thyroxine treatment led to a marked increase in metabolism that was largely UCP1 independent. Chronic thyroxine treatment led to a 1 2 degC increase in body temperature. This increase was also UCP1 independent and was maintained even at lower ambient temperatures. Thus, it was pyrexia, i.e. a defended increase in body temperature, not hyperthermia. In wildtype mice, chronic thyroxine treatment induced a large relative increase in the total amounts of UCP1 in the brown adipose tissue (practically no UCP1 in brite/beige adipose tissue) corresponding to an enhanced thermogenic response to norepinephrine injection. The increased UCP1 amount had minimal effects on thyroxine induced thermogenesis and pyrexia.  These results establish that thyroid thermogenesis is a UCP1 independent process. The fact that the increased metabolism coincides with elevated body temperature and thus with accelerated kinetics accentuates the unsolved issue of the molecular background for thyroid thermogenesis.