Poster Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2014

MIC-1/GDF15, role in physiological and pathological regulation of appetite and body weight (#227)

Vicky Wang-Wei Tsai 1 , Rakesh Manadhar 1 , Ka Ki Michelle Lee-Ng 1 , Hong Ping Zhang 1 , Yasmin Husaini 1 , Shu Lin 2 , Amanda Sainsbury 3 , David A Brown 1 , Samuel N Breit 1
  1. St Vincent's Centre for Applied Medical Research and University of New South Wales, Sydney, NSW, Australia
  2. The Garvan Institute of Medical Research, Sydney, NSW, Australia
  3. The Boden Institute of Obesity, Nutrition, Exercise & Eating Disorders, The University of Sydney, Sydney, NSW, Australia

Macrophage inhibitory cytokine-1 (MIC-1/GDF15) is a divergent member of TGF-b superfamily cytokine that circulates in humans at levels between 150 – 1150 pg/ml. Its increased expression in diseases such as cancer is associated with development of the anorexia/cachexia syndrome. In mice, high serum levels of MIC-1/GDF15 decrease food intake, leading to reduction of both fat and lean mass that is not associated with altered energy expenditure. This anorexic effect is mediated by activation of brainstem nuclei and modified expression of hypothalamic NPY and POMC. Further, viral expression of MIC-1/GDF15 in the hypothalamus, or ICV administration of recombinant MIC-1/GDF15 has the same anorexigenic effects as systemically administration of MIC-1/GDF15.

To further investigate the relative importance of sites of action of MIC-1/GDF15 in the brain, we have selectively lesioned brainstem AP and NTS nuclei activated by systemic administration of MIC-1/GDF15. Lesioned mice became completely resistant to the anorexigenic actions of MIC-1/GDF15, suggesting that these brainstem regions are critical for its anorexic actions.

To determine whether MIC-1/GDF15 might also participate in physiological regulation of appetite, we studied germline MIC-1/GDF15 gene deleted (MIC-1-/-) mice and found that they exhibited increased food intake, body weight and adiposity, an effect that is more marked in female than male mice. Further, this phenotype could be corrected by infusing MIC-1/GDF15 by osmotic minipump, in amounts sufficient to raise their serum levels into the human normal range.

These studies suggested that MIC-1/GDF15 play a role in regulation of food intake and body weight under both physiological and pathological conditions, and brainstem AP and NTS nuclei are critical in this process.