Maratos-Flier Lab & Dr. Jeffrey Flier
Our Major Research Interests
Molecular Regulators of Obesity and Energy Balance in the Periphery and the Brain:
We focus on the following:
- The role of FGF21 in multiple tissues in regulating tissue function and glucose control;
- The role of leptin in feeding, behavior and brain function;
- The role of the hypothalamic Neuropeptide in energy balance the use of mice with MCH deletion as a model of human hyperactivity anorexia nervosa;
- The role of macronutrient diet composition on metabolism; and
- Translational studies of agents that may be clinically useful in weight loss in obese subjects.
Obesity is a significant risk factor for the development of type II diabetes. Although the prevalence of obesity is common, the causes of obesity are poorly understood. Energy balance is regulated by a complex interaction between the periphery and the central nervous system. My major interest is in the mechanisms by which melanin concentrating hormone (MCH) plays a role in energy homeostasis and in integrating signals from the environment. My laboratory initially discovered the orexigenic role of MCH using RT-PCR differential display. We found that mRNA for MCH is elevated in the hypothalamus of the leptin deficient ob/ob mouse, is regulated by fasting and that administration of MCH intracerebroventricularly into rodents led to a rapid and reproducible increase in feeding behavior.
I have subsequently followed up on this finding by generating both a line of mice lacking MCH which are lean, and a line of mice overexpressing MCH which are susceptible to diet induced obesity. Findings with the lean MCH null mice have been of significant interest; in addition to being lean these mice have significant olfactory deficits as demonstrated by behavioral deficits in mating and in tasks involving finding food . This leads me to believe that MCH is important in integrating signals from the environment, an area my laboratory is actively pursuing.
Once the MCH-receptor was identified we mapped expression in the brain of mice and found that it is heavily expressed in regions of the brain involved in olfaction including the olfactory tubercle and piriform cortex suggesting that MCH may be important in integrating olfactory information. Part of the current work in my laboratory is to develop biochemical, behavioral and anatomic correlates for MCH signaling in olfactory areas of the brain.
In addition we have used the MCH null model to further examine the role of MCH in mediating obesity in various obese models. Thus far we have found that absence of MCH attenuates obesity in ob/ob mice as well as in Ay mice which are obese due to abnormal melanocortin signaling; MCH-null mice appear to be resistant to diet induced obesity.
An additional area of interest is determining the role of neuropeptides, including MCH and other orexigenic factors such as NPY and AGRP as well as neuropeptides that diminish appetite such as MSH and CART, in the development of diet-induced obesity in mice.