Investigating the effect of chronic activation of AMP-activated protein kinase in vivo

Abstract

The prevalence of obesity and associated diseases has increased significantly in the last decade, and is now a major public health concern. It is a significant risk factor for many diseases, including cardiovascular disease (CVD) and type 2 diabetes. Characterised by excess lipid accumulation in the white adipose tissue, which drives many associated pathologies, obesity is caused by chronic, whole-organism energy imbalance; when caloric intake exceeds energy expenditure. Whilst lifestyle changes remain the most effective treatment for obesity and the associated metabolic syndrome, incidence continues to rise, particularly amongst children, placing significant strain on healthcare systems, as well as financial burden. AMP-activated protein kinase (AMPK) is widely regarded as a master regulator of energy homeostasis, acting as a cellular ‘fuel gauge’ to maintain intracellular ATP concentrations under conditions of metabolic stress. AMPK is known to promote catabolic pathways, including lipolysis, fatty acid oxidation and glycolysis, whilst inhibiting anabolic pathways in response to energy deprivation. AMPK is a strong therapeutic candidate for the treatment of obesity and the metabolic syndrome, with several studies providing evidence for the amelioration of type 2 diabetes in vivo. In collaboration with AstraZeneca, a novel transgenic mouse model was generated, expressing a gain-of-function mutation in the regulatory γ-subunit of AMPK; D316A, resulting in a constitutively active AMPK complex expressed globally. Initial observations revealed a polycystic kidney-like disease with a possible mouse strain effect, as well as cardiac glycogen accumulation, with no associated conductance defect. The subsequent characterisation of this mouse model revealed a novel role for AMPK activation in the protection from diet-induced obesity, conferred by a significant increase in exercise-independent energy expenditure, driven by UCP1-independent thermogenesis in the subcutaneous white adipose tissue (WATsc). It was found that, on a chow diet, the WATsc resembled classical brown adipose tissue which, when exposed to a high-fat diet, was subjected to transcriptional re-programming leading to the expression of many muscle-related genes associated with calcium/creatine futile cycling. This work highlights a role for AMPK in the protection from obesity, through the alteration of cell fate.