Targeted disruption of the melanocortin-4 receptor results in obesity in mice
D Huszar1, C A Lynch, V Fairchild-Huntress
1Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.
Abstract:
The melanocortin-4 receptor (MC4-R) is a G protein-coupled, seven-transmembrane receptor expressed in the brain. Inactivation of this receptor by gene targeting results in mice that develop a maturity onset obesity syndrome associated with hyperphagia, hyperinsulinemia, and hyperglycemia. This syndrome recapitulates several of the characteristic features of the agouti obesity syndrome, which results from ectopic expression of agouti protein, a pigmentation factor normally expressed in the skin. Our data identify a novel signaling pathway in the mouse for body weight regulation and support a model in which the primary mechanism by which agouti induces obesity is chronic antagonism of the MC4-R.
Insights
Mice lacking the melanocortin-4 receptor (MC4-R) developed obesity, hyperinsulinemia, and hyperglycemia. This suggests MC4-R antagonism is a key mechanism in agouti-induced obesity.
Area of Science:
- Neuroendocrinology
- Molecular Biology
- Genetics
Background:
- The melanocortin-4 receptor (MC4-R) is a brain-expressed G protein-coupled receptor involved in regulating energy balance.
- Agouti protein, normally in skin, can cause obesity when ectopically expressed.
Purpose of the Study:
- To investigate the role of MC4-R in body weight regulation.
- To elucidate the mechanism by which agouti protein induces obesity.
Main Methods:
- Gene targeting to inactivate the MC4-R in mice.
- Phenotypic analysis of MC4-R deficient mice, including metabolic parameters.
Main Results:
- MC4-R inactivation in mice led to maturity onset obesity, hyperphagia, hyperinsulinemia, and hyperglycemia.
- These features resemble the agouti obesity syndrome.
- Data support a novel signaling pathway for body weight regulation.
Conclusions:
- Chronic antagonism of MC4-R by agouti protein is a primary mechanism for agouti-induced obesity.
- MC4-R plays a critical role in central regulation of body weight.
