Fibroblast growth factor 21 (FGF21) reduces body weight, which was attributed to induced energy expenditure (EE). Conflicting data have been published on the role of uncoupling protein 1 (UCP1) in this effect. Therefore, we aimed to revisit the thermoregulatory effects of FGF21 and their implications for body weight regulation. We found that an 8-day treatment with FGF21 lowers body weight to similar extent in both wildtype (WT) and UCP1-deficient (KO) mice fed high-fat diet. In WT mice, this effect is solely due to increased EE, associated with a strong activation of UCP1 and with excess heat dissipated through the tail. This thermogenesis takes place in the interscapular region and can be attenuated by a β-adrenergic inhibitor propranolol. In KO mice, FGF21-induced weight loss correlates with a modest increase in EE, which is independent of adrenergic signaling, and with a reduced energy intake. Interestingly, the gene expression profile of interscapular brown adipose tissue (but not subcutaneous white adipose tissue) of KO mice is massively affected by FGF21, as shown by increased expression of genes encoding triacylglycerol/free fatty acid cycle enzymes. Thus, FGF21 elicits central thermogenic and pyretic effects followed by a concomitant increase in EE and body temperature, respectively. The associated weight loss is strongly dependent on UCP1-based thermogenesis. However, in the absence of UCP1, alternative mechanisms of energy dissipation may contribute, possibly based on futile triacylglycerol/free fatty acid cycling in brown adipose tissue and reduced food intake.
- Klíčová slova
- Brown adipose tissue, Energy expenditure, Fibroblast growth factor 21, Futile fatty acid cycle, Uncoupling protein 1, Weight loss,
- MeSH
- adrenergní látky MeSH
- energetický metabolismus MeSH
- fibroblastové růstové faktory * MeSH
- hmotnostní úbytek * MeSH
- kyseliny mastné neesterifikované * MeSH
- myši obézní MeSH
- myši MeSH
- tělesná hmotnost MeSH
- triglyceridy MeSH
- uncoupling protein 1 genetika MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- adrenergní látky MeSH
- fibroblast growth factor 21 MeSH Prohlížeč
- fibroblastové růstové faktory * MeSH
- kyseliny mastné neesterifikované * MeSH
- triglyceridy MeSH
- uncoupling protein 1 MeSH
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.
- Klíčová slova
- Brown adipose tissue, Fatty acids, Futile substrate cycle, Lipolysis, Re-esterification, UCP1-independent thermogenesis,
- MeSH
- adenosintrifosfát metabolismus MeSH
- hnědá tuková tkáň * metabolismus MeSH
- mastné kyseliny metabolismus MeSH
- myši knockoutované MeSH
- myši MeSH
- termogeneze * MeSH
- triglyceridy metabolismus MeSH
- uncoupling protein 1 genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- adenosintrifosfát MeSH
- mastné kyseliny MeSH
- triglyceridy MeSH
- Ucp1 protein, mouse MeSH Prohlížeč
- uncoupling protein 1 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
- bílá tuková tkáň metabolismus MeSH
- energetický metabolismus MeSH
- fibroblastové růstové faktory genetika metabolismus MeSH
- hnědá tuková tkáň metabolismus MeSH
- lidé MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- obezita genetika metabolismus MeSH
- signální transdukce MeSH
- uncoupling protein 1 genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- fibroblast growth factor 21 MeSH Prohlížeč
- fibroblastové růstové faktory MeSH
- uncoupling protein 1 MeSH
The possibility to use leptin therapeutically for lowering glucose levels in patients with type 1 diabetes has attracted interest. However, earlier animal models of type 1 diabetes are severely catabolic with very low endogenous leptin levels, unlike most patients with diabetes. Here, we aim to test glucose-lowering effects of leptin in novel, more human-like murine models. We examined the glucose-lowering potential of leptin in diabetic models of two types: streptozotocin-treated mice and mice treated with the insulin receptor antagonist S961. To prevent hypoleptinemia, we used combinations of thermoneutral temperature and high-fat feeding. Leptin fully normalized hyperglycemia in standard chow-fed streptozotocin-treated diabetic mice. However, more humanized physiological conditions (high-fat diets or thermoneutral temperatures) that increased adiposity - and thus also leptin levels - in the diabetic mice abrogated the effects of leptin, i.e., the mice developed leptin resistance also in this respect. The glucose-lowering effect of leptin was not dependent on the presence of the uncoupling protein-1 and was not associated with alterations in plasma insulin, insulin-like growth factor 1, food intake or corticosterone but fully correlated with decreased plasma glucagon levels and gluconeogenesis. An important implication of these observations is that the therapeutic potential of leptin as an additional treatment in patients with type 1 diabetes is probably limited. This is because such patients are treated with insulin and do not display low leptin levels. Thus, the potential for a glucose-lowering effect of leptin would already have been attained with standard insulin therapy, and further effects on blood glucose level through additional leptin cannot be anticipated.
- Klíčová slova
- glucagon, insulin receptor antagonist, leptin, thermoneutrality, type 1 diabetes, uncoupling protein 1,
- MeSH
- bílá tuková tkáň metabolismus MeSH
- diabetes mellitus 1. typu metabolismus MeSH
- experimentální diabetes mellitus metabolismus MeSH
- glukagon metabolismus MeSH
- glukoneogeneze MeSH
- hnědá tuková tkáň metabolismus MeSH
- insulinu podobný růstový faktor I metabolismus MeSH
- inzulin metabolismus MeSH
- kortikosteron metabolismus MeSH
- krevní glukóza účinky léků metabolismus MeSH
- kyselina pyrohroznová metabolismus MeSH
- leptin metabolismus farmakologie MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myši knockoutované MeSH
- myši MeSH
- peptidy farmakologie MeSH
- přijímání potravy MeSH
- receptor inzulinu antagonisté a inhibitory MeSH
- spotřeba kyslíku MeSH
- transkriptom MeSH
- uncoupling protein 1 genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- glukagon MeSH
- insulin-like growth factor-1, mouse MeSH Prohlížeč
- insulinu podobný růstový faktor I MeSH
- inzulin MeSH
- kortikosteron MeSH
- krevní glukóza MeSH
- kyselina pyrohroznová MeSH
- LEP protein, human MeSH Prohlížeč
- leptin MeSH
- peptidy MeSH
- receptor inzulinu MeSH
- S961 peptide MeSH Prohlížeč
- Ucp1 protein, mouse MeSH Prohlížeč
- uncoupling protein 1 MeSH
BACKGROUND: Obesity has tremendous impact on the health systems. Its epigenetic bases are unclear. MacroH2A1 is a variant of histone H2A, present in two alternatively exon-spliced isoforms macroH2A1.1 and macroH2A1.2, regulating cell plasticity and proliferation, during pluripotency and tumorigenesis. Their role in adipose tissue plasticity is unknown. RESULTS: Here, we show evidence that macroH2A1.1 protein levels in the visceral adipose tissue of obese humans positively correlate with BMI, while macroH2A1.2 is nearly absent. We thus introduced a constitutive GFP-tagged transgene for macroH2A1.2 in mice, and we characterized their metabolic health upon being fed a standard chow diet or a high fat diet. Despite unchanged food intake, these mice exhibit lower adipose mass and improved glucose metabolism both under a chow and an obesogenic diet. In the latter regimen, transgenic mice display smaller pancreatic islets and significantly less inflammation. MacroH2A1.2 overexpression in the mouse adipose tissue induced dramatic changes in the transcript levels of key adipogenic genes; genomic analyses comparing pre-adipocytes to mature adipocytes uncovered only minor changes in macroH2A1.2 genomic distribution upon adipogenic differentiation and suggested differential cooperation with transcription factors. MacroH2A1.2 overexpression markedly inhibited adipogenesis, while overexpression of macroH2A1.1 had opposite effects. CONCLUSIONS: MacroH2A1.2 is an unprecedented chromatin component powerfully promoting metabolic health by modulating anti-adipogenic transcriptional networks in the differentiating adipose tissue. Strategies aiming at enhancing macroH2A1.2 expression might counteract excessive adiposity in humans.
- Klíčová slova
- Adipose tissue, Histone variants, Obesity, macroh2a1.2,
- MeSH
- adipogeneze MeSH
- buněčná diferenciace MeSH
- buněčné linie MeSH
- dieta s vysokým obsahem tuků MeSH
- fenotyp MeSH
- glukózový toleranční test MeSH
- histony genetika metabolismus MeSH
- index tělesné hmotnosti MeSH
- inhibitor p21 cyklin-dependentní kinasy genetika metabolismus MeSH
- inzulin metabolismus MeSH
- játra patologie MeSH
- kůže patologie MeSH
- lidé MeSH
- metabolické inženýrství MeSH
- myši inbrední C57BL MeSH
- myši transgenní MeSH
- myši MeSH
- pankreas patologie MeSH
- tuková tkáň cytologie metabolismus MeSH
- uncoupling protein 1 genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- histony MeSH
- inhibitor p21 cyklin-dependentní kinasy MeSH
- inzulin MeSH
- macroH2A histone MeSH Prohlížeč
- uncoupling protein 1 MeSH
