News & Research

    University of Colorado, Denver, Aurora, Colorado

Lipoprotein lipase in the CNS: impact on body weight and energy balance

General Research Subject: Both Type 1 And Type 2 Diabetes

Focus: Insulin Action

Type of Grant: Basic Science

Project Start Date: January 1, 2010

Project End Date: December 31, 2012

Research Description

Obesity is in epidemic proportions, and demonstrates no signs of reduced incidence. Weight loss is not only difficult to achieve but even more difficult to sustain long term, implying that fat mass is defended. It therefore becomes increasingly important to understand how body weight and fat mass are regulated. The central nervous system plays a critical role in body weight regulation. Lipoprotein lipase (LPL) is an enzyme in adipose tissue and muscle that controls the uptake of fatty acids from the breakdwon of circulating triglyceride-rich lipoproteins for lipid storage and/or oxidation; however, LPL is also present throughout the nervous system. In the brain, LPL mRNA is found in neurons in the hippocampus, hypothalamus, pyramidal cortex, and the Purkinje cells of the cerebellum. 

We have generated a novel mouse model with neuron-specific deletion of LPL (NEXLPL-/-). In NEXLPL-/- mice, LPL mRNA is reduced in several brain regions including the hippocampus and hypothalamus. By 6 months these mice are severely obese and have reduced energy expenditure. Of interest heterozygous mice for neuron-specific LPL deficiency develop obesity between 6 and 12 months and have a preceding period of increased food intake. In this grant a combined molecular/cellular and whole animal physiological approach will be used to study the importance of perturbed lipid metabolism in the brain and its role in the regulation of body weight and energy balance.

Researcher Profile

What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes? 

Obesity is not only present in a large percentage of patients with type 2 diabetes but is a strong predictor of new onset type 2 diabetes and the complications of diabetes. Moreover, obesity is in epidemic proportions, and demonstrates no signs of reduced incidence. It therefore becomes increasingly important to understand how body weight and fat mass are regulated. The CNS plays a critical role in body weight regulation. Lipoprotein lipase (LPL) is an enzyme in adipose tissue and muscle that controls the uptake of fatty acids from the breakdown of circulating triglyceride-rich lipoproteins for lipid storage and/or oxidation; however, LPL is also present throughout the nervous system. In the brain, LPL mRNA is found in neurons in the hippocampus and hypothalamus. We have generated a novel mouse model with neuron-specific deletion of LPL (NEXLPL-/-). 

By 6 months these mice are severely obese and have reduced energy expenditure. Of interest heterozygous mice for neuron-specific LPL deficiency develop obesity between 6 and 12 months and have a preceding period of increased food intake. In this grant a combined molecular/cellular and whole animal physiological approach will be used to study the importance of perturbed lipid metabolism in the brain and its role in the regulation of body weight and energy balance. We hope that the results of these studies will provide more insights into how body weight and energy balance are regulated with subsequent approaches that will reduce the incidence and prevalence of obesity and type 2 diabetes in humans.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond? 

We hope that the results of these studies of perturbed lipid metabolism in the brain of mice will provide new insights into how body weight and energy balance are regulated with subsequent approaches that will help you to prevent and/or treat type 2 diabetes and its complications.

Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts? 

I have had type 1 diabetes for 57 years, and have always been interested in how the pathophysiology and complications of type 1 and type 2 diabetes differ. My research background is predominantly in the areas of lipid metabolism and obesity with a desire to understand more fully how to prevent and treat obesity and related lipid disorders. I am excited about our new mouse model in that new pathways of body weight regulation and energy balance are at our door-step. This funding will be the first support for this type of work with hopefully new data to be generated that will launch an expanded effort to follow.

In what direction do you see the future of diabetes research going? 

Research in diabetes needs to be directed to better understand the pathophysiology of type 1 and type 2 diabetes so that methods of prevention can be tested and proven successful. These might include the development of new biomarkers, lifestyle modification, vaccines, and/or pharmaceutical interventions. A similar scenario should be encouraged in the area of the complications of diabetes.