AMP-Activated Protein Kinase (AMPK) Regulates Energy Metabolism through Modulating Thermogenesis in Adipose Tissue

Abstract

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.

AMPK activation protects astrocytes from hypoxia‑induced cell death

“…This difference was expected due to the direct mechanism of action of A-769662, as compared to the indirect mechanism of 2dG. The inhibition of Acc is known to reduce cellular energy consumption, decreasing the highly energy intensive anabolic process of lipid biosynthesis (35,36). Furthermore, AMPK activation with A-769662 led to an inhibition of Akt and the mTORc1 target protein, RPS6.…”

Exercise Improves Outcomes of Surgery on Fatty Liver in Mice

“…42 Novel, allosteric AMPK activators are being developed and show promising hepatic effects in animal models of diabetes. 43,44 Other classes (ie, not targeting AMPK) of 'exercise-mimetics' are also being evaluated in humans; at the current stage, it is unclear, which of these will remain clinically viable and some (such as the PPARd activator GW1516) had to be abandoned because of unwanted effects, 38,45 Importantly, single infusions of AICAR are considered as safe (based on data from >4000 patients, [39][40][41] and multiple dosing likewise has been associated with an acceptable safety profile. 46 Steatosis seems to particularly predispose to the development of non-cirrhotic HCC 47 and thereby directly increases the demand for liver surgery.…”

Low-protein/high-carbohydrate diet induces AMPK-dependent canonical and non-canonical thermogenic response in subcutaneous adipose tissue

“…Of note, the expression of skeletal muscle-associated genes was induced in subcutaneous white adipocytes from mice with constitutively induced AMPK (Pollard et al, 2019). Chronic genetic or pharmacological AMPK activation results in protection against dietinduced obesity and induction of energy-dissipating phenotype in white adipose tissue (Pollard et al, 2019;Wu et al, 2018;Zhu et al, 2016). In line with these findings, our experiments carried out in mice with a loss of function of AMPK, specifically in adipose depots (AKO mice), confirmed its role in eliciting the acquirement of canonical and non-canonical(muscular) brown-like signatures in sWAT.…”

“…Related animal experiments were approved by the Animal Care and Use Committee of the Shanghai Institute of Materia Medica, where the experiments were conducted. All animals were housed in a temperature-controlled room (22 ± 2 °C), with a light/dark cycle of 12 h. Adipose tissue-specific AMPKα1/α2 double-KO mice (referred to as AKO mice) were generated as previously described (Wu et al, 2018). Male AKO mice and age-matched AMPKα1/α2-floxed littermates were randomly divided into four groups.…”