OBJECTIVE: Administration of FGF21 to mice reduces body weight and increases body temperature. The increase in body temperature is generally interpreted as hyperthermia, i.e. a condition secondary to the increase in energy expenditure (heat production). Here, we examine an alternative hypothesis: that FGF21 has a direct pyrexic effect, i.e. FGF21 increases body temperature independently of any effect on energy expenditure. METHODS: We studied the effects of FGF21 treatment on body temperature and energy expenditure in high-fat-diet-fed and chow-fed mice exposed acutely to various ambient temperatures, in high-fat diet-fed mice housed at 30 °C (i.e. at thermoneutrality), and in mice lacking uncoupling protein 1 (UCP1). RESULTS: In every model studied, FGF21 increased body temperature, but energy expenditure was increased only in some models. The effect of FGF21 on body temperature was more (not less, as expected in hyperthermia) pronounced at lower ambient temperatures. Effects on body temperature and energy expenditure were temporally distinct (daytime versus nighttime). FGF21 enhanced UCP1 protein content in brown adipose tissue (BAT); there was no measurable UCP1 protein in inguinal brite/beige adipose tissue. FGF21 increased energy expenditure through adrenergic stimulation of BAT. In mice lacking UCP1, FGF21 did not increase energy expenditure but increased body temperature by reducing heat loss, e.g. a reduced tail surface temperature. CONCLUSION: The effect of FGF21 on body temperature is independent of UCP1 and can be achieved in the absence of any change in energy expenditure. Since elevated body temperature is a primary effect of FGF21 and can be achieved without increasing energy expenditure, only limited body weight-lowering effects of FGF21 may be expected.

• Klíčová slova
• Beiging/browning, Body temperature control, Obesity, Thermoneutrality, UCP1,
• MeSH
• dieta s vysokým obsahem tuků škodlivé účinky   MeSH
• energetický metabolismus účinky léků   MeSH
• fibroblastové růstové faktory aplikace a dávkování   farmakologie   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• tělesná teplota účinky léků   MeSH
• uncoupling protein 1 nedostatek   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• 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
• Ucp1 protein, mouse MeSH Prohlížeč
• 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

Whether active UCP1 can reduce ROS production in brown-fat mitochondria is presently not settled. The issue is of principal significance, as it can be seen as a proof- or disproof-of-principle concerning the ability of any protein to diminish ROS production through membrane depolarization. We therefore undertook a comprehensive investigation of the significance of UCP1 for ROS production, by comparing the ROS production in brown-fat mitochondria isolated from wildtype mice (that display membrane depolarization) or from UCP1(-/-) mice (with a high membrane potential). We tested the significance of UCP1 for glycerol-3-phosphate-supported ROS production by three methods (fluorescent dihydroethidium and the ESR probe PHH for superoxide, and fluorescent Amplex Red for hydrogen peroxide), and followed ROS production also with succinate, acyl-CoA or pyruvate as substrate. We studied the effects of the reverse electron flow inhibitor rotenone, the UCP1 activity inhibitor GDP, and the uncoupler FCCP. We also examined the effect of a physiologically induced increase in UCP1 amount. We noted GDP effects that were not UCP1-related. We conclude that only ROS production supported by exogenously added succinate was affected by the presence of active UCP1; ROS production supported by any other tested substrate (including endogenously generated succinate) was unaffected. This conclusion indicates that UCP1 is not involved in control of ROS production in brown-fat mitochondria. Extrapolation of these data to other tissues would imply that membrane depolarization may not necessarily decrease physiologically relevant ROS production. This article is a part of a Special Issue entitled: 18th European Bioenergetics Conference (Biochim. Biophys. Acta, Volume 1837, Issue 7, July 2014).

• Klíčová slova
• Brown adipose tissue mitochondria, Cold acclimation, Glycerol-3-phosphate dehydrogenase, Reactive oxygen species, Succinate, Uncoupling protein 1,
• MeSH
• elektronová paramagnetická rezonance MeSH
• glycerolfosfáty farmakologie   MeSH
• guanosindifosfát farmakologie   MeSH
• hnědá tuková tkáň metabolismus   MeSH
• imunoblotting MeSH
• iontové kanály genetika   metabolismus   MeSH
• karbonylkyanid-p-trifluormethoxyfenylhydrazon farmakologie   MeSH
• kyselina jantarová farmakologie   MeSH
• kyselina pyrohroznová farmakologie   MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• mitochondriální proteiny genetika   metabolismus   MeSH
• mitochondrie účinky léků   metabolismus   fyziologie   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• nízká teplota MeSH
• peroxid vodíku metabolismus   MeSH
• protonové ionofory farmakologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• spotřeba kyslíku účinky léků   MeSH
• superoxidy metabolismus   MeSH
• uncoupling protein 1 MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• alpha-glycerophosphoric acid MeSH Prohlížeč
• glycerolfosfáty MeSH
• guanosindifosfát MeSH
• iontové kanály MeSH
• karbonylkyanid-p-trifluormethoxyfenylhydrazon MeSH
• kyselina jantarová MeSH
• kyselina pyrohroznová MeSH
• mitochondriální proteiny MeSH
• peroxid vodíku MeSH
• protonové ionofory MeSH
• reaktivní formy kyslíku MeSH
• superoxidy MeSH
• Ucp1 protein, mouse MeSH Prohlížeč
• uncoupling protein 1 MeSH

We are facing a revival of the strategy to counteract obesity and associated metabolic disorders by inducing thermogenesis mediated by mitochondrial uncoupling protein-1 (UCP1). Thus, the main focus is on the adaptive non-shivering thermogenesis occurring both in the typical depots of brown adipose tissue (BAT) and in UCP1-containing cells that could be induced in white adipose tissue (WAT). Because contribution of WAT to resting metabolic rate is relatively small, the possibility to reduce adiposity by enhancing energy expenditure in classical white adipocytes is largely neglected. However, several pieces of evidence support a notion that induction of energy expenditure based on oxidation of fatty acids (FA) in WAT may be beneficial for health, namely: (i) studies in both humans and rodents document negative association between oxidative capacity of mitochondria in WAT and obesity; (ii) pharmacological activation of AMPK in rats as well as cold-acclimation of UCP1-ablated mice results in obesity resistance associated with increased oxidative capacity in WAT; and (iii) combined intervention using long-chain n-3 polyunsaturated FA (omega 3) and mild calorie restriction exerted synergism in the prevention of obesity in mice fed a high-fat diet; this was associated with strong hypolipidemic and insulin-sensitizing effects, as well as prevention of inflammation, and synergistic induction of mitochondrial oxidative phosphorylation (OXPHOS) and FA oxidation, specifically in epididymal WAT. Importantly, these changes occurred without induction of UCP1 and suggested the involvement of: (i) futile substrate cycle in white adipocytes, which is based on lipolysis of intracellular triacylglycerols and re-esterification of FA, in association with the induction of mitochondrial OXPHOS capacity, β-oxidation, and energy expenditure; (ii) endogenous lipid mediators (namely endocannabinoids, eicosanoids, prostanoids, resolvins, and protectins) and their cognate receptors; and (iii) AMP-activated protein kinase in WAT. Quantitatively, the strong induction of FA oxidation in WAT in response to the combined intervention is similar to that observed in the transgenic mice rendered resistant to obesity by ectopic expression of UCP1 in WAT. The induction of UCP1-independent FA oxidation and energy expenditure in WAT in response to the above physiological stimuli could underlie the amelioration of obesity and low-grade WAT inflammation, and it could reduce the release of FA from adipose tissue and counteract harmful consequences of lipid accumulation in other tissues. In this respect, new combination treatments may be designed using naturally occurring micronutrients (e.g. omega 3), reduced calorie intake or pharmaceuticals, exerting synergism in the induction of the mitochondrial OXPHOS capacity and stimulation of lipid catabolism in white adipocytes, and improving metabolic flexibility of WAT. The role of mutual interactions between adipocytes and immune cells contained in WAT in tissue metabolism should be better characterised. This article is part of a Special Issue entitled Brown and White Fat: From Signaling to Disease.

• MeSH
• bílá tuková tkáň cytologie   metabolismus   MeSH
• energetický metabolismus * MeSH
• fenotyp MeSH
• iontové kanály metabolismus   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• metabolismus lipidů * MeSH
• mitochondriální proteiny metabolismus   MeSH
• mitochondrie fyziologie   MeSH
• myši MeSH
• oxidační stres MeSH
• oxidativní fosforylace * MeSH
• signální transdukce MeSH
• tukové buňky cytologie   metabolismus   MeSH
• uncoupling protein 1 MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• iontové kanály MeSH
• mitochondriální proteiny MeSH
• UCP1 protein, human MeSH Prohlížeč
• Ucp1 protein, mouse MeSH Prohlížeč
• Ucp1 protein, rat MeSH Prohlížeč
• uncoupling protein 1 MeSH

To test if mitochondrial uncoupling in white adipocytes is responsible for obesity resistance of the aP2-Ucp transgenic mice expressing ectopic uncoupling protein 1 (UCPI) in white fat, mitochondrial membrane potential (delta psi(m)) was estimated by flow cytometry in adipocytes isolated from gonadal fat. Ectopic UCP1 (approximately 0.8 mol UCP1/mol respiratory chain) decreased the delta psi(m) and rendered the potential sensitive to GDP and fatty acids. These ligands of UCP1 had no effect on delta psi(m) in white adipocytes from non-transgenic mice, suggesting that the function of endogenous UCP2 in adipocytes was not affected. The results support the hypothesis that mitochondrial uncoupling in white fat may prevent development of obesity.

• MeSH
• fluorescenční barviva metabolismus   MeSH
• guanosindifosfát metabolismus   MeSH
• iontové kanály MeSH
• karbonylkyanid-p-trifluormethoxyfenylhydrazon farmakologie   MeSH
• mastné kyseliny metabolismus   MeSH
• membránové potenciály genetika   MeSH
• membránové proteiny genetika   metabolismus   MeSH
• membránové transportní proteiny * MeSH
• mitochondriální proteiny * MeSH
• mitochondrie genetika   MeSH
• myši transgenní MeSH
• myši MeSH
• obezita metabolismus   MeSH
• permeabilita buněčné membrány účinky léků   MeSH
• proteiny metabolismus   MeSH
• průtoková cytometrie MeSH
• transportní proteiny genetika   metabolismus   MeSH
• tukové buňky metabolismus   MeSH
• uncoupling protein 1 MeSH
• uncoupling protein 2 MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fluorescenční barviva MeSH
• guanosindifosfát MeSH
• iontové kanály MeSH
• karbonylkyanid-p-trifluormethoxyfenylhydrazon MeSH
• mastné kyseliny MeSH
• membránové proteiny MeSH
• membránové transportní proteiny * MeSH
• mitochondriální proteiny * MeSH
• proteiny MeSH
• transportní proteiny MeSH
• Ucp1 protein, mouse MeSH Prohlížeč
• Ucp2 protein, mouse MeSH Prohlížeč
• uncoupling protein 1 MeSH
• uncoupling protein 2 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

In vitro experiments suggest that stimulation of lipolysis by catecholamines in adipocytes depends on the energy status of these cells. We tested whether mitochondrial uncoupling proteins (UCPs) that control the efficiency of ATP production could affect lipolysis and noradrenaline signalling in white fat in vivo. The lipolytic effect of noradrenaline was lowered by ectopic UCP1 in white adipocytes of aP2-Ucp1 transgenic mice, overexpressing the UCP1 gene from the aP2 gene promoter, reflecting the magnitude of UCP1 expression, the impaired stimulation of cAMP levels by noradrenaline and the reduction of the ATP/ADP ratio in different fat depots. Thus only subcutaneous but not epididymal fat was affected. UCP1 also down-regulated the expression of hormone-sensitive lipase and lowered its activity, and altered the expression of trimeric G-proteins in adipocytes. The adipose tissue content of the stimulatory G-protein alpha subunit was increased while that of the inhibitory G-protein alpha subunits decreased in response to UCP1 expression. Our results support the idea that the energy status of cells, and the ATP/ADP ratio in particular, modulates the lipolytic effects of noradrenaline in adipose tissue in vivo. They also demonstrate changes at the G-protein level that tend to overcome the reduction of lipolysis when ATP level in adipocytes is low. Therefore, respiratory uncoupling may exert a broad effect on hormonal signalling in adipocytes.

• MeSH
• adenosindifosfát metabolismus   MeSH
• adenosintrifosfát metabolismus   MeSH
• AMP cyklický metabolismus   MeSH
• DNA primery MeSH
• genotyp MeSH
• hepatocyty enzymologie   MeSH
• iontové kanály MeSH
• lipasa genetika   MeSH
• lipolýza * MeSH
• membránové proteiny genetika   fyziologie   MeSH
• mitochondriální proteiny MeSH
• myši inbrední C57BL MeSH
• myši transgenní MeSH
• myši MeSH
• noradrenalin metabolismus   MeSH
• proteiny vázající GTP metabolismus   MeSH
• regulace genové exprese enzymů MeSH
• sekvence nukleotidů MeSH
• transportní proteiny genetika   fyziologie   MeSH
• tuková tkáň enzymologie   metabolismus   MeSH
• uncoupling protein 1 MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenosindifosfát MeSH
• adenosintrifosfát MeSH
• AMP cyklický MeSH
• DNA primery MeSH
• iontové kanály MeSH
• lipasa MeSH
• membránové proteiny MeSH
• mitochondriální proteiny MeSH
• noradrenalin MeSH
• proteiny vázající GTP MeSH
• transportní proteiny MeSH
• Ucp1 protein, mouse MeSH Prohlížeč
• uncoupling protein 1 MeSH

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
• 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

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

Cachexia represents a fatal energy-wasting syndrome in a large number of patients with cancer that mostly results in a pathological loss of skeletal muscle and adipose tissue. Here we show that tumor cell exposure and tumor growth in mice triggered a futile energy-wasting cycle in cultured white adipocytes and white adipose tissue (WAT), respectively. Although uncoupling protein 1 (Ucp1)-dependent thermogenesis was dispensable for tumor-induced body wasting, WAT from cachectic mice and tumor-cell-supernatant-treated adipocytes were consistently characterized by the simultaneous induction of both lipolytic and lipogenic pathways. Paradoxically, this was accompanied by an inactivated AMP-activated protein kinase (Ampk), which is normally activated in peripheral tissues during states of low cellular energy. Ampk inactivation correlated with its degradation and with upregulation of the Ampk-interacting protein Cidea. Therefore, we developed an Ampk-stabilizing peptide, ACIP, which was able to ameliorate WAT wasting in vitro and in vivo by shielding the Cidea-targeted interaction surface on Ampk. Thus, our data establish the Ucp1-independent remodeling of adipocyte lipid homeostasis as a key event in tumor-induced WAT wasting, and we propose the ACIP-dependent preservation of Ampk integrity in the WAT as a concept in future therapies for cachexia.

• MeSH
• bílá tuková tkáň účinky léků   metabolismus   MeSH
• bílé tukové buňky účinky léků   metabolismus   MeSH
• kachexie etiologie   metabolismus   MeSH
• kultivované buňky MeSH
• lipogeneze účinky léků   MeSH
• lipolýza účinky léků   MeSH
• metabolismus lipidů účinky léků   MeSH
• myši MeSH
• nádory komplikace   metabolismus   MeSH
• peptidové fragmenty farmakologie   MeSH
• proteinkinasy aktivované AMP metabolismus   farmakologie   MeSH
• proteiny regulující apoptózu účinky léků   metabolismus   MeSH
• techniky in vitro MeSH
• termogeneze účinky léků   MeSH
• uncoupling protein 1 účinky léků   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• Cidea protein, mouse MeSH Prohlížeč
• peptidové fragmenty MeSH
• Prkab1 protein, mouse MeSH Prohlížeč
• proteinkinasy aktivované AMP MeSH
• proteiny regulující apoptózu MeSH
• Ucp1 protein, mouse MeSH Prohlížeč
• uncoupling protein 1 MeSH