Endocrine Abstracts

Survival requires the ability to adapt to cycles of feast and famine, yet the underlying mechanisms to maintain metabolic balance during extremes of nutrient excess remain poorly understood. We recently discovered that the classic growth factor FGF1 is induced in white adipose tissue (WAT) in response to high-fat-diet (HFD) and repressed during fastong, pointing to an unexpected metabolic function. Thus, FGF1 participates in both fed-state and fasted-state responses. In WAT, FGF1 is induced by HFD through a PPAR-γ dependent mechanism and thus is also responsive to PPARg drugs such as Actos and Avandia. Mice with a deficiency in FGF1, when challenged with a HFD, develop an aggressive diabetic phenotype, resulting from adipose that is unable to expand, which progressively becomes inflamed, fibrotic and necrotic and is simply unable to adapt to nutrient stress.

As loss of FGF1 by knockout results in a diabetic phenotype, we speculated that increasing FGF1 levels by direct injection in diabetic mice, could potentially have anti-diabetic effects. As a proteoglycan binding protein, endogenous FGF1 is normally locally restricted. Upon ’endocrinization’ of FGF1 by simple injection into the body of obese diabetic mice we found potent glucose lowering and insulin sensitizing effects. Thus, more that 30 years after its discovery as a growth factor, ‘endocrinization’ of FGF1 in a diabetic mouse, uncovers a potent yet hidden insulin sensitizing activity with great potential as a new therapy in the treatment of metabolic disease.