Abstract
Pharmacological treatment of recombinant growth differentiation factor 15 (GDF15) proteins reduces body weight in obese rodents and primates. Paradoxically, circulating GDF15 levels are increased in obesity. To investigate the role of endogenous GDF15 in obesity development, we put GDF15 knockout mice and wildtype controls on high fat diet for the mice to develop diet-induced obesity. Compared to wildtype animals, GDF15 knockout mice were more prone to high fat diet-induced obesity. Male knockout mice showed worse glucose tolerance, lower locomotor activity and lower metabolic rate than wildtype mice. Additionally, GDF15 deficiency increased occurrences of high fat diet-induced skin lesions. Our data suggests that endogenous GDF15 has a protective role in obesity development and lack of GDF15 aggravates the progression of obesity and associated pathological conditions. Elevated GDF15 levels in obesity may have resulted from a response to overcome GDF15 resistance.
Highlights
Obesity is a major public health burden associated with life-threatening comorbidities [1, 2]
Male growth differentiation factor 15 (GDF15) knockout mice were more prone to high fat diet-induced obesity than wildtype mice
GDF15 deficiency in the knockout mice was verified by measuring circulating mouse GDF15 levels in wildtype and knockout mice (S1 Fig)
Summary
Obesity is a major public health burden associated with life-threatening comorbidities [1, 2]. GDF15 is a transforming growth factor- β (TGF-β) superfamily member that has recently generated broad interest as a new target to develop pharmacotherapies for obesity and related comorbidities. Reports from multiple groups have clearly demonstrated that treatment of recombinant GDF15 proteins reduces body weight and improves glucose tolerance in obese rodents and primates [5,6,7,8,9,10]. The pharmacological studies are consistent with previous reports of GDF15 transgenic mice being resistant to high fat diet-induced obesity (DIO) and glucose intolerance [11,12,13,14], supporting a therapeutic role of high levels of exogenous GDF15 in obesity and diabetes management. The biological function of endogenous GDF15 is not completely clear. The reported phenotypes are mild and definitive understanding of the biological role of endogenous GDF15 remains elusive.
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