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.