Emerging Role of AMPK in Brown and Beige Adipose Tissue (BAT): Implications for Obesity, Insulin Resistance, and Type 2 Diabetes

Abstract

Ablation of AMPK in mouse adipocytes results in cold intolerance, a reduction in non-shivering thermogenesis in brown adipose tissue (BAT), and the development of non-alcoholic fatty liver disease (NAFLD) and insulin resistance; effects associated with a defect in mitochondrial specific autophagy (mitophagy) within BAT. The effects of a β3-adrenergic agonist on the induction of BAT thermogenesis and the browning of white adipose tissue (WAT) are also blunted in mice lacking adipose tissue AMPK. A specific AMPK activator, A-769662, also results in the activation of BAT and the browning of WAT, effects which may involve demethylation of the PR domain containing 16 (Prdm16) promoter region, which is important for BAT development. AMPK plays an important role in the development and maintenance of brown and beige adipose tissue. Adipose tissue AMPK is reduced in people with insulin resistance, consistent with findings that mice lacking adipocyte AMPK develop greater NAFLD and insulin resistance. These data suggest that pharmacologically targeting adipose tissue AMPK may represent a promising strategy to enhance energy expenditure and reduce circulating glucose and lipids, which may be effective for the treatment of NAFLD and T2D.

AMPK: a balancer of the renin–angiotensin system

“…The ACE is critical in the generation of angiotensin II (AngII) [71], it plays the main role in the classic RAS pathway [72]. AMPK has been proved to associate with many kinds of diseases, for instance cardiovascular disease [9,63], metabolic syndrome [56,67], renal pathophysiology [73], and aging [44]. So there should be some association between ACE and AMPK.…”

Targeting the Inositol Pyrophosphate Biosynthetic Enzymes in Metabolic Diseases

“…AMPK stimulates the catabolic pathways to generate ATP while conserving the remaining ATP by switching off the anabolic pathways [99]. AMPK stimulates energy expenditure [29,[100][101][102][103][104][105][106][107][108][109], which maintains normal body weight, insulin sensitivity and liver-metabolism [103,[110][111][112][113][114][115][116][117]. Deregulation of AMPK is observed in obesity, diabetes and other metabolic diseases [29,[100][101][102][103][104][105][106][107][108][109][110][111][112][113][114][115]117].…”

“…Conversely, AMPK inhibits fatty acid biosynthesis, lipogenesis, cholesterol synthesis and gluconeogenesis by modulating ACC, sterol regulatory element binding protein 1C (SREBP1C), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and CREB-regulated transcription co-activator 2 (CRTC2) or forkhead box transcription factors (FoxO1), respectively [99]. Moreover, AMPK promotes adipose tissue browning mediated thermogenic energy expenditure [116]. For example, various agents like apelin, miRNA-455, resveratrol, cryptotanshinone, medicarpin and AICAR increase AMPK activity and adipocyte browning [116].…”

Molecular Mechanisms of Adipogenesis: The Anti-Obesogenic Role of AMP-Activated Protein Kinase and Recently Reported Plant Products

“…Therefore, the protein is a key therapeutic target for the treatment of major metabolic disorders including obesity and type-2 diabetes [103]. As adipogenesis is an energy consuming process, AMPK regulates the inhibition of expression of FAS, adipocyte specific pre-adipocytes, highlighting the potential role of AMPK in the inhibition of adipogenesis [111] In addition, AMPK has also been shown to be pertinent in the britening of WAT thereby increasing the energy expenditure through thermogenesis [112,113]. It has also been reported that the activity of AMPK increases during the differentiation of brown adipocytes and that targeting AMPK by short interfering RNAs (siRNAs), inhibits the differentiation of pre-adipocytes into mature brown adipocytes [16,114].…”

“…Upstream kinases of AMPK include Liver Kinase B1 (LKB1), mouse protein 25 (MO25) and STE-related adaptor (STRAD). LKB1[112,118], is part of a heterotrimeric protein.For activation, it needs the binding of other two upstream kinases of AMPK, STRAD and MO25 to form a heterotrimeric complex. It directly activates AMPK by phosphorylating Thr172 of α subunit.…”