The intestine plays a pivotal role in lipid metabolism and energy balance. It is the portal for dietary nutrients, the source of apolipoprotein B-containing chylomicra, and an endocrine organ that signals current nutritional status to other tissues to maintain homeostasis and promote metabolic efficiency. However, many molecular mechanisms involved in these processes remain elusive. The long-term goal of our research is to understand how intestinal lipid processing regulates systemic lipid metabolism and energy balance. The overall objective of this proposal is to elucidate the mechanism(s) by which acyl CoA:monoacylglycerol acyltransferase-2 (MGAT2) regulates whole body energy balance. Mice deficient in MGAT2 (Mgat2-/- mice) display a remarkable resistance to obesity and related metabolic disorders induced by high-fat feeding. In contrast to the well- established role of the intestine in regulating food intake and nutrient assimilation, the phenotype of Mgat2-/- mice suggests a previously unrecognized role of the intestine in modulating energy expenditure. Among known MGAT enzymes, MGAT2 is highly expressed in the intestine of human and mouse. MGAT activity is best known for its role in the absorption of dietary fat, because it catalyzes triacylglycerol re-synthesis, a required step for the formation of chylomicra, which deliver dietary fat to peripheral tissues. Despite consuming and absorbing normal amounts of fat, Mgat2-/- mice are protected from excessive weight gain on a high-fat diet. Compared to their control littermates, however, these mice expend significantly more energy. The difference in energy expenditure increases, as dietary fat increases. Although Mgat2-/- mice absorb normal quantities of fat, more of the dietary fat is absorbed from the distal intestine, thereby delaying the entry of dietary fat into the circulation. In addition, their postprandial levels of glucose-dependent insulinotropic peptide (GIP) are lower, whereas glucagon-like peptide1 (GLP1) levels are higher than in controls. Both gut hormones can affect energy balance. Thus, we hypothesize that MGAT2 coordinates the uptake and processing of lipid for chylomicron formation in enterocytes and modulates the secretion of GIP and GLP1 from enteroendocrine cells. As such, intestinal MGAT2 directs the delivery of dietary fat toward storage for efficient assimilation of this calorie-dense nutrient. To test our hypothesis, in Aim 1, we will elucidate the role of MGAT2 in intestinal lipid metabolism, chylomicron formation, and gut hormone release.
In Aim 2, we will determine the functional consequences of lacking MGAT2 on the distribution of dietary fat.
In Aim 3, we will assess the overall impact of intestinal MGAT2 on systemic energy balance using mice that express MGAT2 only in the intestine and mice that lack MGAT2 in the same intestine-specific manner. By completing these aims, we will advance our understanding of how intestinal lipid metabolism modulates systemic energy balance, which would be important, because it would build a new paradigm for understanding fat assimilation, a fundamental physiological process that is crucial for survival during lean times but may lead to excessive body fat in periods of abundance.

Public Health Relevance

Triacylglycerol metabolism in the intestine is essential for the assimilation of high-energy substrates, essential fatty acids, and fat-soluble nutrients and vitamins. It also is a central player in obesity and associated metabolic disorders. The proposed research will use multiple genetic models to advance our understanding in the field of intestinal lipid metabolism and energy balance. This work will both increase knowledge about a central component of metabolism as well as provide insights into potential therapies for addressing the obesity epidemic.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK088210-02
Application #
8244992
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Maruvada, Padma
Project Start
2011-04-01
Project End
2016-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
2
Fiscal Year
2012
Total Cost
$322,988
Indirect Cost
$105,488
Name
University of Wisconsin Madison
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715