AMP-activated protein kinase activation in skeletal muscle modulates exercise-induced uncoupled protein 1 expression in brown adipocyte in mouse model.

Aerobic exercise is an effective intervention in preventing obesity and is also an important factor associated with thermogenesis. There is an increasing interest in the factors and mechanisms induced by aerobic exercise that can influence the metabolism and thermogenic activity in an individual. Recent studies suggest that exercise induced circulating factors (known as 'exerkines'), which are able to modulate activation of brown adipose tissue (BAT) and browning of white adipose tissue. However, the underlying molecular mechanisms associated with the effect of exercise-induced peripheral factors on BAT activation remain poorly understood. Furthermore, the role of exercise training in BAT activation is still debatable. Hence, the purpose of our study is to assess whether exercise training affects the expression of uncoupled protein 1 (UCP1) in brown adipocytes via release of different blood factors. Four weeks of exercise training significantly decreased the body weight gain and fat mass gain. Furthermore, trained mice exhibit higher levels of energy expenditure and UCP1 expression than untrained mice. Surprisingly, treatment with serum from exercise-trained mice increased the expression of UCP1 in differentiated brown adipocytes. To gain a better understanding of these mechanisms, we analysed the conditioned media obtained after treating the C2C12 myotubes with an AMP-activated protein kinase (AMPK) activator (AICAR; 5-aminoimidazole-4-carboxamide ribonucleotide), which leads to an increased expression of UCP1 when added to brown adipocytes. Our observations suggest the possibility of aerobic exercise-induced BAT activation via activation of AMPK in skeletal muscles. KEY POINTS: Exercise promotes thermogenesis by activating uncoupling protein 1 (UCP1), which leads to a decrease in the body weight gain and body fat content. However, little is known about the role of exerkines in modulating UCP1 expression and subsequent brown adipose tissue (BAT) activation. Four weeks of voluntary wheel-running exercise reduces body weight and fat content. Exercise induces the increase in AMP-activated protein kinase (AMPK) and slow-type muscle fibre marker genes in skeletal muscles and promotes UCP1 expression in white and brown adipose tissues. Incubation of brown adipocytes with serum isolated from exercise-trained mice significantly increased their UCP1 gene and protein levels; moreover, conditioned media of AMPK-activator-treated C2C12 myotubes induces increased UCP1 expression in brown adipocytes. These results show that aerobic exercise-induced skeletal muscle AMPK has a significant effect on UCP1 expression in BAT.

Kim HJ ，Kim YJ ，Seong JK 《-》

Platycodin D, a novel activator of AMP-activated protein kinase, attenuates obesity in db/db mice via regulation of adipogenesis and thermogenesis.

Platycodi Radix (root of Platycodon grandiflorum) and its active compound platycodin D (PD) has been previously shown to possess anti-obesity properties, but the underlying mechanisms remain poorly understood. The present study was aimed to evaluate the anti-obese effect of PD and reveal its mechanism of action. Genetically obese db/db mice were orally treated with PD for 4 weeks, and body weight gain, adipose tissue weight, serum parameters were measured. Then, assays on adipogenic factors, thermogenic factors, and AMP-activated protein kinase (AMPK) pathway were performed in PD-treated 3T3-L1 murine adipocytes, human adipose-derived mesenchymal stem cells (hAMSCs), and primary cultured brown adipocytes. PD treatment attenuated body weight gain, suppressed white adipose tissue weight and improved obesity-related serum parameters in db/db mice. Two major adipogenic factors, peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer binding protein α (C/EBPα) were decreased by PD treatment in WAT of db/db mice, 3T3-L1 adipocytes and hAMSCs. In BAT of db/db mice and primary cultured brown adipocytes, PD treatment elevated the expressions of uncoupled protein 1 (UCP1) and peroxisome proliferator-activated receptor γ coactivator 1 α (PCG1α), the key regulators of BAT-associated thermogenesis. In addition, PD activated AMPKα both in vivo and in vitro. However, when AMPK was inhibited by compound C, PD treatment failed to suppress adipogenic factors and increase thermogenic factors. PD improved obesity in db/db mice by AMPK-associated decrease of adipogenic markers including PPARγ and C/EBPα. PD increased thermogenic factors such as UCP1 and PGC1α in db/db mice and primary cultured brown adipocytes. AMPK inhibition nullified the effects of PD, suggesting its anti-adipogenic and thermogenic actions were dependent on AMPK pathway activation.

Kim HL ，Park J ，Jung Y ，Ahn KS ，Um JY ... -  《-》

An obesogenic diet impairs uncoupled substrate oxidation and promotes whitening of the brown adipose tissue in rats.

Brown adipose tissue (BAT) is rich in mitochondria containing uncoupling protein 1 (UCP1), and dissipates energy through thermogenesis. However, even though BAT mass and its UCP1 content increase in rodents chronically fed a high-fat sucrose-enriched (HFS) diet, marked expansion of adiposity still occurs in these animals, suggesting insufficient BAT-mediated HFS diet-induced thermogenesis. Thus, the objective of this study was to investigate the metabolic and molecular mechanisms that regulate BAT thermogenesis in HFS-induced obesity. To accomplish this, rats were fed either a standard chow or HFS diet for 8 weeks. Subsequently, glucose and fatty acid metabolism and the molecular mechanisms underlying these processes were assessed in freshly isolated primary BAT adipocytes. Despite increasing BAT mass and its UCP1 content, the HFS diet reduced uncoupled glucose and palmitate oxidation in BAT adipocytes. It also markedly diminished tyrosine hydroxylase content and lipolysis in these cells. Conversely, glucose uptake, lactate production, glycerol incorporation into lipids, palmitate incorporation into triacylglycerol (TAG), phosphoenolpyruvate carboxykinase and glycerol kinase levels, and lipoprotein lipase and cluster of differentiation 36 gene expression were increased. In summary, a HFS diet enhanced glyceroneogenesis and shifted BAT metabolism toward TAG synthesis by impairing UCP1-mediated substrate oxidation and by enhancing fatty acid esterification in intact brown adipocytes. These adaptive metabolic responses to chronic HFS feeding attenuated BAT thermogenic capacity and favoured the development of obesity. KEY POINTS: Despite increasing brown adipose tissue (BAT) mass and levels of thermogenic proteins such as peroxisome proliferator-activated receptor γ coactivator 1α, carnitine palmitoyltransferase 1B and uncoupling protein 1 (UCP1), an obesogenic high-fat sucrose-enriched (HFS) diet attenuated uncoupled glucose and fatty acid oxidation in brown adipocytes. Brown adipocytes diverted glycerol and fatty acids toward triacylglycerol (TAG) synthesis by elevating the cellular machinery that promotes fatty acid uptake along with phosphoenolpyruvate carboxykinase and glycerol kinase levels. The HFS diet increased glucose uptake that supported lactate production and provided substrate for glyceroneogenesis and TAG synthesis in brown adipocytes. Impaired UCP-1-mediated thermogenic capacity and enhanced TAG storage in BAT adipocytes were consistent with reduced adipose triglyceride lipase and tyrosine hydroxylase levels in HFS diet-fed animals.

Da Eira D ，Jani S ，Ceddia RB 《-》

β -Lapachone Regulates Obesity through Modulating Thermogenesis in Brown Adipose Tissue and Adipocytes: Role of AMPK Signaling Pathway.

Kwak HJ ，Jeong MY ，Um JY ，Park J ... -  《-》

Cold acclimation and pioglitazone combined increase thermogenic capacity of brown and white adipose tissues but this does not translate into higher energy expenditure in mice.

Valdivia LFG ，Castro É ，Eichler RADS ，Moreno MF ，de Sousa É ，Jardim GFR ，Peixoto ÁS ，Moraes MN ，Castrucci AML ，Nedergaard J ，Petrovic N ，Festuccia WT ，Reckziegel P ... -  《-》