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Cordycepin promotes browning of white adipose tissue through an AMP-activated protein kinase (AMPK)-dependent pathway.

ABSTRACT: Obesity is a worldwide epidemic. Promoting browning of white adipose tissue (WAT) contributes to increased energy expenditure and hence counteracts obesity. Here we show that cordycepin (Cpn), a natural derivative of adenosine, increases energy expenditure, inhibits weight gain, improves metabolic profile and glucose tolerance, decreases WAT mass and adipocyte size, and enhances cold tolerance in normal and high-fat diet-fed mice. Cpn markedly increases the surface temperature around the inguinal WAT and turns the inguinal fat browner. Further investigations show that Cpn induces the development of brown-like adipocytes in inguinal and, to a less degree, epididymal WAT depots. Cpn also increases the expression of uncoupling protein 1 (UCP1) and other thermogenic genes in WAT and 3T3-L1 differentiated adipocytes, in which AMP-activated protein kinase (AMPK) plays an important role. Our results provide novel insights into the function of Cpn in regulating energy balance, and suggest a potential utility of Cpn in the treatment of obesity.

SUBMITTER: Qi G

PROVIDER: S-EPMC6361849 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Cordycepin promotes browning of white adipose tissue through an AMP-activated protein kinase (AMPK)-dependent pathway.

Qi Guihong G Zhou Yue Y Zhang Xiaopo X Yu Jiaqi J Li Xin X Cao Xiaoxue X Wu Chongming C Guo Peng P

Acta pharmaceutica Sinica. B 20181017 1

Obesity is a worldwide epidemic. Promoting browning of white adipose tissue (WAT) contributes to increased energy expenditure and hence counteracts obesity. Here we show that cordycepin (Cpn), a natural derivative of adenosine, increases energy expenditure, inhibits weight gain, improves metabolic profile and glucose tolerance, decreases WAT mass and adipocyte size, and enhances cold tolerance in normal and high-fat diet-fed mice. Cpn markedly increases the surface temperature around the inguina ...[more]

PMID: 30766785

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Project description:Obesity occurs when excess energy accumulates in white adipose tissue (WAT), whereas brown adipose tissue (BAT), which is specialized in dissipating energy through thermogenesis, potently counteracts obesity. White adipocytes can be converted to thermogenic "brown-like" cells (beige cells; WAT browning) under various stimuli, such as cold exposure. AMP-activated protein kinase (AMPK) is a crucial energy sensor that regulates energy metabolism in multiple tissues. However, the role of AMPK in adipose tissue function, especially in the WAT browning process, is not fully understood. To illuminate the effect of adipocyte AMPK on energy metabolism, we generated Adiponectin-Cre-driven adipose tissue-specific AMPK α1/α2 KO mice (AKO). These AKO mice were cold intolerant and their inguinal WAT displayed impaired mitochondrial integrity and biogenesis, and reduced expression of thermogenic markers upon cold exposure. High-fat-diet (HFD)-fed AKO mice exhibited increased adiposity and exacerbated hepatic steatosis and fibrosis and impaired glucose tolerance and insulin sensitivity. Meanwhile, energy expenditure and oxygen consumption were markedly decreased in the AKO mice both in basal conditions and after stimulation with a β3-adrenergic receptor agonist, CL 316,243. In contrast, we found that in HFD-fed obese mouse model, chronic AMPK activation by A-769662 protected against obesity and related metabolic dysfunction. A-769662 alleviated HFD-induced glucose intolerance and reduced body weight gain and WAT expansion. Notably, A-769662 increased energy expenditure and cold tolerance in HFD-fed mice. A-769662 treatment also induced the browning process in the inguinal fat depot of HFD-fed mice. Likewise, A-769662 enhanced thermogenesis in differentiated inguinal stromal vascular fraction (SVF) cells via AMPK signaling pathway. In summary, a lack of adipocyte AMPKα induced thermogenic impairment and obesity in response to cold and nutrient-overload, respectively, whereas chronic AMPK activation by A-769662 promoted WAT browning in inguinal WAT and protected against HFD-induced obesity and related metabolic dysfunction. These findings reveal a vital role for adipocyte AMPK in regulating the browning process in inguinal WAT and in maintaining energy homeostasis, which suggests that the targeted activation of adipocyte AMPK may be a promising strategy for anti-obesity therapy.

Project description:Background: Salvianolic acid A (Sal A), a natural polyphenolic compound extracted from Radix Salvia miltiorrhiza (Danshen), exhibits exceptional pharmacological activities against cardiovascular diseases. While a few studies have reported anti-obesity properties of Sal A, the underlying mechanisms are largely unknown. Given the prevalence of obesity and promising potential of browning of white adipose tissue to combat obesity, recent research has focused on herbal ingredients that may promote browning and increase energy expenditure. Purpose: The present study was designed to investigate the protective antiobesity mechanisms of Sal A, in part through white adipose browning. Methods: Both high-fat diet (HFD)-induced obese (DIO) male mice model and fully differentiated C3H10T1/2 adipocytes from mouse embryo fibroblasts were employed in this study. Sal A (20 and 40 mg/kg) was administrated to DIO mice by intraperitoneal injection for 13-weeks. Molecular mechanisms mediating effects of Sal A were evaluated. Resluts: Sal A treatment significantly attenuated HFD-induced weight gain and lipid accumulation in epididymal fat pad. Uncoupling protein 1 (UCP-1), a specialized thermogenic protein and marker for white adipocyte browning, was significantly induced by Sal A treatment in both white adipose tissues and cultured adipocytes. Further mechanistic investigations revealed that Sal A robustly reversed HFD-decreased AMP-activated protein kinase (AMPK) phosphorylation and sirtuin 1 (SIRT1) expression in mice. Genetically silencing either AMPK or SIRT1 using siRNA abolished UCP-1 upregulation by Sal A. AMPK silencing significantly blocked Sal A-increased SIRT1 expression, while SIRT1 silencing did not affect Sal A-upregulated phosphorylated-AMPK. These findings indicate that AMPK was involved in Sal A-increased SIRT1. Conclusion: Sal A increases white adipose tissue browning in HFD-fed male mice and in cultured adipocytes. Thus, Sal is a potential natural therapeutic compound for treating and/or preventing obesity.

Project description:BackgroundStromal adipocytes and tumor breast epithelial cells undergo a mutual metabolic adaptation within tumor microenvironment. Therefore, browning and lipolysis occur in cancer associated adipocytes (CAA). However, the paracrine effects of CAA on lipid metabolism and microenvironment remodeling remain poorly understood.MethodsTo analyze these changes, we evaluated the effects of factors in conditioned media (CM) derived from explants of human breast adipose tissue from tumor (hATT) or normal (hATN) on morphology, degree of browning, the levels of adiposity, maturity, and lipolytic-related markers in 3T3-L1 white adipocytes by Western blot, indirect immunofluorescence and lipolytic assay. We analyzed subcellular localization of UCP1, perilipin 1 (Plin1), HSL and ATGL in adipocytes incubated with different CM by indirect immunofluorescence. Additionally, we evaluated changes in adipocyte intracellular signal pathways.ResultsWe found that adipocytes incubated with hATT-CM displayed characteristics that morphologically resembled beige/brown adipocytes with smaller cell size and higher number of small and micro lipid droplets (LDs), with less triglyceride content. Both, hATT-CM and hATN-CM, increased Pref-1, C/EBPβ LIP/LAP ratio, PPARγ, and caveolin 1 expression in white adipocytes. UCP1, PGC1α and TOMM20 increased only in adipocytes that were treated with hATT-CM. Also, hATT-CM increased the levels of Plin1 and HSL, while decreased ATGL. hATT-CM modified the subcellular localization of the lipolytic markers, favoring their relative content around micro-LDs and induced Plin1 segregation. Furthermore, the levels of p-HSL, p-ERK and p-AKT increased in white adipocytes after incubation with hATT-CM.ConclusionsIn summary, these findings allow us to conclude that adipocytes attached to the tumor could induce white adipocyte browning and increase lipolysis as a means for endocrine/paracrine signaling. Thus, adipocytes from the tumor microenvironment exhibit an activated phenotype that could have been induced not only by secreted soluble factors from tumor cells but also by paracrine action from other adipocytes present in this microenvironment, suggesting a "domino effect".

Dataset Information

Cordycepin promotes browning of white adipose tissue through an AMP-activated protein kinase (AMPK)-dependent pathway.

Publications

Cordycepin promotes browning of white adipose tissue through an AMP-activated protein kinase (AMPK)-dependent pathway.

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