Oral Presentation Australian & New Zealand Obesity Society 2014 Annual Scientific Meeting

Macrophage inhibitory cytokine 1 (MIC-1/GDF15), a novel regulator of body weight and appetite and a potential therapeutic for obesity (#52)

Vicky Wang-Wei Tsai 1 , Laurence Macia 2 , Rakesh Manandhar 1 , Fredrik Wiklund 3 , Henrik Grönberg 3 , Nancy Pedersen 3 , Michel Lee-Ng 1 , Hong Ping Zhang 1 , David Brown 1 , Herbert Herzog 2 , Amanda Salis 4 , Samuel N Breit 1
  1. St Vincent's Centre for Applied Medical Research, Darlinghurst, NSW, Australia
  2. The Garvan Institute of Medical Research Australia, Sydney, NSW, Australia
  3. Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
  4. The Boden Institute of Obesity, Nutrition, Exercise & Eating Disorders, The University of Sydney, Sydney, NSW, Australia

MIC-1/GDF15, a distant member of TGFβ superfamily circulates in normals at 150-1150 pg/ml. These levels can rise dramatically in diseases like advanced cancer, where it acts on appetite centres in the brain, leading to anorexia/cachexia. Further, modestly elevated levels of MIC-1/GDF15 are correlated with decreased insulin sensitivity in obese pre-diabetics or diabetic subjects, and serum levels of MIC-1/GDF15 predict the development of complications of type 2 diabetes.

To determine if MIC-1/GDF15 plays a role in physiological regulation of energy intake/expenditure, we studied MIC-1/GDF15 germline gene knockout mice (MIC-1-/-).  They have increased body weight and visceral fat associated with increased food intake and, in females, reduced basal energy expenditure. Further, their body weight and food intake were corrected when MIC-1/GDF15 serum levels were raised to normal human physiological level by administration of small amounts of recombinant protein. Additionally, transgenic mice overexpressing MIC-1/GDF15 have a lean phenotype with a reduced body weight, fat and lean mass due to reduction in food intake. Importantly, under either normal or high-fat-diet, these mice had better glucose tolerance; lower insulin levels and were resistant to dietary and genetic-induced obesity.

To investigate whether MIC-1/GDF15 may also regulate energy intake in humans, we examined MIC-1/GDF15 serum levels and BMI in non-obese monozygotic twins, the use of which eliminates the effect of heritable and familial factors, and consequently increases the sensitivity of our analysis. We found that the within-twin-pair difference in serum MIC-1/GFDF15 levels was strongly correlated with the within-twin-pair difference in BMI. These data suggest that MIC-1/GDF15 regulates BMI independently of genetic background, which is consistent with data obtained in mice.

Our studies suggest that MIC-1/GDF15, is a physiological as well as disease associated regulator of body weight and appetite and might be a novel therapeutic for treatment of obesity and related diseases.