AMP-activated protein kinase (AMPK), a master regulator of metabolism, is activated by cellular energy stress. It restores the cellular energy balance by upregulating catabolic, ATP producing pathways and by downregulating anabolic, ATP utilising pathways. It is a therapeutic target in diabetes due to its ability to increase glucose uptake and in non-alcoholic fatty liver disease, due to inhibition of hepatic de novo lipogenesis. Both diseases are strongly correlated with obesity, but as yet AMPK has not been targeted in obesity. Obesity is the excessive accumulation of fat, which is mostly stored in adipose tissue. To determine whether adipose tissue AMPK could be targeted in the treatment of obesity it is important to increase our understanding of the effects of activation of AMPK in adipose tissue. Previous work from the Carling lab has shown that a mouse with genetic, global constitutive activation of AMPK, called the AMPKγ1D316A mouse, is protected from diet induced obesity due to increased ATP uncoupling in the white adipose tissue (WAT) through skeletal muscle associated mechanisms of thermogenesis.
In this work, AMPKγ1D316A adipose tissue or adipocytes were unable to retain the AMPKγ1D316A characteristics when removed from the environment of the AMPKγ1D316A mouse, suggesting that the phenotype is not tissue autonomous. Meanwhile, pharmacological activation of AMPK in a skeletal muscle myocyte led to an increase in adipogenesis, strengthening the link between AMPK activation and the adipocyte-myocyte relationship. Pharmacological activation of AMPK during adipose tissue derived stem cell differentiation suppressed adipogenesis, which was found to be independent of AMPK’s inhibition of lipogenesis. Instead, AMPK acted in the initial phases of adipogenesis whilst slowing proliferation. AMPK activation in embryonic stem cell adipogenesis also suppressed differentiation, and maintained higher levels of stem cell markers. Pharmacological AMPK activation also led to a dose dependent reduction in adipocyte lipid droplet size which may be due to its inhibition of lipogenesis, or reflect the disruption of terminal differentiation, preventing the formation of a mature adipocyte with large lipid droplets. However, the suppression of adipogenesis and reduction in lipid droplet size with AMPK activation were accompanied by a decrease in leptin gene expression, indicating that AMPK activation may lead to lipodystrophy in adipose tissue. This work furthers our knowledge of the AMPKγ1D316A mouse and the effect of pharmacological AMPK activation in adipogenesis, and leaves more to be explored.