Medical Student Research Fellowship for Summer 2009

Mentor: Elizabeth J. Parks, PhD
Department: Center for Human Nutrition and Dept. of Internal Medicine
Room number: L5.112
Mail Code: 9052
Phone number: (214) 648-2054
E-mail: Elizabeth.parks@utsouthwestern.edu
Project I title: "Pharmacological blockage of a selective cannabinoid-1 receptor in a non-human primate model"

Animal subjects IRB approved project number (where applicable):
Southwestern Foundation for Primate Research IACUC protocol # 1203PC 0

Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects). An animal-based study in a primate model of obesity and insulin resistance.

Brief Description of Project:
This is a funded study of the effect of a CB1 antagonism to reduce food intake and change metabolic efficiency to improve insulin resistance. The student will work with a postdoctoral fellow to learn techniques which include analysis of fatty acids and lipoproteins, lipid biochemistry and metabolism studied using basic biochemistry, gas chromatography/mass spectrometry (GC/MS) and mathematical modeling.

CURRENT PROJECT ABSTRACT: Endocannabinoids (ECs) are locally-produced, short-lived, endogenous amides and esters of long-chain polyunsaturated fatty acids produced by adipocytes. These novel lipid mediators and their endogenous receptors make up the EC system which controls feeding behaviour via the CNS, and peripheral energy metabolism both directly and indirectly. Upregulation of the EC system has been shown in obesity - both obese humans' and rodent models have elevated levels of ECs in the blood and adipose tissue. Antagonist treatment of the EC receptor (CB1r) has been shown to reduce co-morbidities associated with metabolic syndrome. The purpose of the present study is to test the effect of the EC antagonist, SR141716, to reduce adipose lipid synthesis and increase fatty acid efflux leading to weight loss in a non-human primate model of obesity and insulin resistance. Male baboons (n=12, 10y, 28-35 kg) will be randomly assigned SR141716 (15 mg/d) or placebo daily for 8 wks. The placebo animals will be pairfed to match food intake to their body weight matched treated animals. Before and after treatment, plasma will be analyzed for concentrations of glucose, NEFA, insulin, leptin, HMW-adiponectin, resistin, cortisol, and IL-6. Adipose tissue will be harvested to assess histologic changes and molecular expression assays will be performed, in addition to the measurement of insulin sensitivity and metabolic labeling to quantitate fatty acid flux in vivo. The effect of treatment on adipose will be analyzed using repeated-measures ANOVA and each animal will serve as its own control. We hypothesize that compared to placebo, SR141716 treatment will induce significantly more weight loss, upregulate the expression of genes related to EC degradation and lipid oxidation, and reduce expression of genes related to fatty acid and TG synthesis. SR141716-induced gene expression will result in metabolic alterations consistent with increased tissue-TG turnover, resulting in a net increase in lipolysis. These results will expand the understanding of the EC system in obesity and serve as a basis for the targeted development of treatments to reduce risks for CVD.

Project II title: "Dietary macronutrient composition, weight loss, and liver substrate metabolism"

Human subjects IRB approved project number (where applicable):
PROTOCOL: 062007-025 entitled, "Body weight and liver health"

Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects). A patient-based research study in individuals with the metabolic syndrome.

Brief Description of Project:
This is an NIH-funded study of the effect of nutrient partitioning (glucose and fat metabolism, insulin sensitivity, etc) in patients with non-alcoholic fatty liver disease. The student has the opportunity to work with 1 of 4 different faculty collaborators to learn techniques that range from clinical trial management, clinical research methods (whole body calorimetry, body composition, activity measurements, etc) to basic biochemistry in the lab to investigate the metabolism of glucose, lipid, mineral metabolism, sleep disorders in obesity, gas chromatography/mass spectrometry (GC/MS) or NMR.

Previous Research Activities or Publications with Medical Students:
Medical students and biomedical summer interns assisted us with the following studies:

Zhu Q, Anderson GW, Mucha GT, Parks, EJ, Metkowski JK, Mariash CN: The Spot 14 protein is required for de novo lipid synthesis in the lactating mammary gland. Endocrinology, 146(8):3343-3350, 2005.
Figueroa A, Milla C, Parks EJ, Schwarzenberg SJ, Moran A: Abnormal lipid levels in cystic fibrosis. Amer J Clinical Nutrition, 75:1005-1011, 2002.
Parks EJ, Skogen LA, Timlin MT, Dingfelder CS: Acute impact of sugars on fatty acid synthesis.
J Nutrition, 138:1039-1046, 2008.
Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ: Sources of fatty acids contributing to hepatic steatosis in nonalcoholic fatty liver disease. J Clinical Investigation, 115(5):1343-1351, 2005.
Parks EJ, Schneider TL, Baar RA: Meal-feeding studies in mice: effects of different diets
on blood lipids and energy expenditure. Comparative Medicine, 55(1):13-17, 2005.