OBJECTIVE: Classical ATP-independent non-shivering thermogenesis enabled by uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) is activated, but not essential for survival, in the cold. It has long been suspected that futile ATP-consuming substrate cycles also contribute to thermogenesis and can partially compensate for the genetic ablation of UCP1 in mouse models. Futile ATP-dependent thermogenesis could thereby enable survival in the cold even when brown fat is less abundant or missing. METHODS: In this study, we explore different potential sources of UCP1-independent thermogenesis and identify a futile ATP-consuming triglyceride/fatty acid cycle as the main contributor to cellular heat production in brown adipocytes lacking UCP1. We uncover the mechanism on a molecular level and pinpoint the key enzymes involved using pharmacological and genetic interference. RESULTS: ATGL is the most important lipase in terms of releasing fatty acids from lipid droplets, while DGAT1 accounts for the majority of fatty acid re-esterification in UCP1-ablated brown adipocytes. Furthermore, we demonstrate that chronic cold exposure causes a pronounced remodeling of adipose tissues and leads to the recruitment of lipid cycling capacity specifically in BAT of UCP1-knockout mice, possibly fueled by fatty acids from white fat. Quantification of triglyceride/fatty acid cycling clearly shows that UCP1-ablated animals significantly increase turnover rates at room temperature and below. CONCLUSION: Our results suggest an important role for futile lipid cycling in adaptive thermogenesis and total energy expenditure.

• Keywords
• Brown adipose tissue, Fatty acids, Futile substrate cycle, Lipolysis, Re-esterification, UCP1-independent thermogenesis,
• MeSH
• Adenosine Triphosphate metabolism   MeSH
• Adipose Tissue, Brown * metabolism   MeSH
• Fatty Acids metabolism   MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Thermogenesis * MeSH
• Triglycerides metabolism   MeSH
• Uncoupling Protein 1 genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adenosine Triphosphate MeSH
• Fatty Acids MeSH
• Triglycerides MeSH
• Ucp1 protein, mouse MeSH Browser
• Uncoupling Protein 1 MeSH

Branched-chain amino acids (BCAA) are essential amino acids utilized in anabolic and catabolic metabolism. While extensively studied in obesity and diabetes, recent evidence suggests an important role for BCAA metabolism in cancer. Elevated plasma levels of BCAA are associated with an increased risk of developing pancreatic cancer, namely pancreatic ductal adenocarcinoma (PDAC), a tumor with one of the highest 1-year mortality rates. The dreadful prognosis for PDAC patients could be attributable also to the early and frequent development of cancer cachexia, a fatal host metabolic reprogramming leading to muscle and adipose wasting. We propose that BCAA dysmetabolism is a unifying component of several pathological conditions, i.e., obesity, insulin resistance, and PDAC. These conditions are mutually dependent since PDAC ranks among cancers tightly associated with obesity and insulin resistance. It is also well-established that PDAC itself can trigger insulin resistance and new-onset diabetes. However, the exact link between BCAA metabolism, development of PDAC, and tissue wasting is still unclear. Although tissue-specific intracellular and systemic metabolism of BCAA is being intensively studied, unresolved questions related to PDAC and cancer cachexia remain, namely, whether elevated circulating BCAA contribute to PDAC etiology, what is the biological background of BCAA elevation, and what is the role of adipose tissue relative to BCAA metabolism during cancer cachexia. To cover those issues, we provide our view on BCAA metabolism at the intracellular, tissue, and whole-body level, with special emphasis on different metabolic links to BCAA intermediates and the role of insulin in substrate handling.

• Keywords
• Adipose tissue, BCAA metabolism, Cancer cachexia, Insulin resistance, PDAC,
• MeSH
• Diabetes Mellitus * MeSH
• Carcinoma, Pancreatic Ductal * etiology   pathology   MeSH
• Insulin Resistance * MeSH
• Cachexia etiology   MeSH
• Humans MeSH
• Pancreatic Neoplasms * pathology   MeSH
• Obesity complications   metabolism   MeSH
• Amino Acids, Branched-Chain metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Amino Acids, Branched-Chain MeSH

In mammals, the white adipocyte is a cell type that is specialized for storage of energy (in the form of triacylglycerols) and for energy mobilization (as fatty acids). White adipocyte metabolism confers an essential role to adipose tissue in whole-body homeostasis. Dysfunction in white adipocyte metabolism is a cardinal event in the development of insulin resistance and associated disorders. This Review focuses on our current understanding of lipid and glucose metabolic pathways in the white adipocyte. We survey recent advances in humans on the importance of adipocyte hypertrophy and on the in vivo turnover of adipocytes and stored lipids. At the molecular level, the identification of novel regulators and of the interplay between metabolic pathways explains the fine-tuning between the anabolic and catabolic fates of fatty acids and glucose in different physiological states. We also examine the metabolic alterations involved in the genesis of obesity-associated metabolic disorders, lipodystrophic states, cancers and cancer-associated cachexia. New challenges include defining the heterogeneity of white adipocytes in different anatomical locations throughout the lifespan and investigating the importance of rhythmic processes. Targeting white fat metabolism offers opportunities for improved patient stratification and a wide, yet unexploited, range of therapeutic opportunities.

• MeSH
• Adipocytes, White metabolism   MeSH
• Homeostasis MeSH
• Humans MeSH
• Disease Management * MeSH
• Lipid Metabolism physiology   MeSH
• Obesity metabolism   therapy   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

BACKGROUND: Cachexia worsens long-term prognosis of patients with heart failure (HF). Effective treatment of cachexia is missing. We seek to characterize mechanisms of cachexia in adipose tissue, which could serve as novel targets for the treatment. METHODS: The study was conducted in advanced HF patients (n = 52; 83% male patients) undergoing heart transplantation. Patients with ≥7.5% non-intentional body weight (BW) loss during the last 6 months were rated cachectic. Clinical characteristics and circulating markers were compared between cachectic (n = 17) and the remaining, BW-stable patients. In epicardial adipose tissue (EAT), expression of selected genes was evaluated, and a combined metabolomic/lipidomic analysis was performed to assess (i) the role of adipose tissue metabolism in the development of cachexia and (ii) potential impact of cachexia-associated changes on EAT-myocardium environment. RESULTS: Cachectic vs. BW-stable patients had higher plasma levels of natriuretic peptide B (BNP; 2007 ± 1229 vs. 1411 ± 1272 pg/mL; P = 0.010) and lower EAT thickness (2.1 ± 0.8 vs. 2.9 ± 1.4 mm; P = 0.010), and they were treated with ~2.5-fold lower dose of both β-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACE/ARB-inhibitors). The overall pattern of EAT gene expression suggested simultaneous activation of lipolysis and lipogenesis in cachexia. Lower ratio between expression levels of natriuretic peptide receptors C and A was observed in cachectic vs. BW-stable patients (0.47 vs. 1.30), supporting activation of EAT lipolysis by natriuretic peptides. Fundamental differences in metabolome/lipidome between BW-stable and cachectic patients were found. Mitochondrial phospholipid cardiolipin (CL), specifically the least abundant CL 70:6 species (containing C16:1, C18:1, and C18:2 acyls), was the most discriminating analyte (partial least squares discriminant analysis; variable importance in projection score = 4). Its EAT levels were higher in cachectic as compared with BW-stable patients and correlated with the degree of BW loss during the last 6 months (r = -0.94; P = 0.036). CONCLUSIONS: Our results suggest that (i) BNP signalling contributes to changes in EAT metabolism in cardiac cachexia and (ii) maintenance of stable BW and 'healthy' EAT-myocardium microenvironment depends on the ability to tolerate higher doses of both ACE/ARB inhibitors and β-adrenergic blockers. In line with preclinical studies, we show for the first time in humans the association of cachexia with increased adipose tissue levels of CL. Specifically, CL 70:6 could precipitate wasting of adipose tissue, and thus, it could represent a therapeutic target to ameliorate cachexia.

• Keywords
• Adipose tissue, Cardiac cachexia, Cardiolipin, Heart failure, Lipolysis, Natriuretic peptides,
• MeSH
• Angiotensin Receptor Antagonists MeSH
• Angiotensin-Converting Enzyme Inhibitors MeSH
• Cachexia * etiology   MeSH
• Cardiolipins MeSH
• Humans MeSH
• Natriuretic Peptides MeSH
• Heart Failure * complications   MeSH
• Adipose Tissue * MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Angiotensin Receptor Antagonists MeSH
• Angiotensin-Converting Enzyme Inhibitors MeSH
• Cardiolipins MeSH
• Natriuretic Peptides MeSH

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.

• MeSH
• Adipose Tissue, White metabolism   MeSH
• Energy Metabolism MeSH
• Fibroblast Growth Factors genetics   metabolism   MeSH
• Adipose Tissue, Brown metabolism   MeSH
• Humans MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Obesity genetics   metabolism   MeSH
• Signal Transduction MeSH
• Uncoupling Protein 1 genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• fibroblast growth factor 21 MeSH Browser
• Fibroblast Growth Factors MeSH
• Uncoupling Protein 1 MeSH