Medical Student Research Fellowship for Summer 2005

Mentor: Dr. Abhimanyu Garg and Dr. Anil Agarwal
Department: Internal Medicine
Room number: Y3.218
Mail Code: 9052
Phone number: (214) 648-8734
E-mail:
Project title: Molecular Basis of Adipose Tissue Heterogeneity

Human subjects IRB approved project number (where applicable): 082004-066

Animal subjects IRB approved project number (where applicable): NA

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)

Patient-based Research

Brief Description of Project:

Adipose tissue is found in various locations throughout the human body. Beyond the function of triglyceride storage and release, adipocytes secrete various factors called adipocytokines. Examples of these include leptin, resistin, and adiponectin (1). These molecular signals have been shown to control various functions including appetite, lipolysis, and inflammatory response.

Obesity and lipodystrophy are the two extremes of adipocyte dysfunction. Either condition leads to the clinical presentation of the metabolic syndrome; this includes insulin resistance, hypertriglyceridemia, development of DM2, and coronary artery disease (2,3). While fatty acids accumulate in ectopic sites such as the liver and skeletal muscle in both conditions, this occurs by over-engorgement of adipocytes with lipid droplets in obesity and occurs by the absence or inability of adipocytes to accumulate lipid droplets in lipodystrophy (3,4,5).

According to NHANES 1999-2000, there was an estimated 31% of US adults (?20 yrs) - approximately 59 million people - that were found to be obese (BMI >30) (6). Some estimates show that national costs attributed to medical expenses resulting from obesity (BMI>30) and overweight (BMI 25-29.9) reached $92.6 billion (in 2002 dollars) for the year of 1998 (7). The enormity of this health problem is clearly evident.

By gaining a better understanding of the adipocyte, better preventative and therapeutic interventions can be developed. This can be done by studying specific disease models whose pathology lies in specific known defects.

In our earlier research on congenital generalized lipodystrophies, it was discovered that different genetic mutations caused distinct adipose tissue distributions.

Type Gene of Mutation Gene Function
CGL1 AGPAT2 (1-acylglycerol-3-phosphate-O-acyltransferase 2) One of six known isoforms of AGPAT enzymes - important in triglyceride and phospholipid biosynthesis
CGL2 BSCL2 (Berardinelli-Seip Congenital Lipodystrophy 2) Function unknown

In CGL1, there was a deficiency of metabolically active adipose tissue depots and preservation of mechanically functioning adipose tissue depots.

In CGL2, there was a deficiency in both types of adipose tissue.

Metabolically Active Adipose Depot Mechanical Adipose Depot
Most Subcutaneous (SC)
Intra-Abdominal (Omental, Mesenteric,
Retroperitoneal)
Intrathoracic
Bone Marrow Retro-Orbital Scalp (SC)
Buccal (SC) Palm/Sole (SC)
Vulvar (SC) Periarticular
Epidural Crista galli
Pericalyceal

With the substantial absence of adipose tissue depots, both types of syndromes left patients with severe metabolic abnormalities including severely elevated serum triglyceride levels, marked hyperinsulinemia, hepatosplenomegaly, and acromegaloid features. However, these patients have extremely low levels of adipocytokines (5,8,9,10,11,12).

The underlying molecular basis of the heterogeneity in function across differing adipose tissue depots remains undefined. Moreover, the effect of adipose tissue heterogeneity on conditions such as obesity and its accompanying co-morbidities remains unclear.

The primary goal of this study is to characterize the heterogeneity of human adipose tissue collected from different anatomic regions using global gene and protein expression.

Research Question:
Is there a statistically significant differential expression of the AGPAT2 and BSCL2 genes (at the mRNA and protein levels) in metabolically-active vs. mechanical adipose tissue depots?

REFERENCES
1. Guerre-Millo M. Adipose tissue and adipokines: for better or worse. Diabetes Metab 2004; 30: 13-19.
2. Garg A. Acquired and genetic lipodystrophies. N Engl J Med 2004. 350;1220-1234.
3. James PT, Leach R, Kalamara E, Shayeghi M. The Worldwide Obesity Epidemic. Obesity Research 2001; 9 (Suppl 4): 228S-233S.
4. Fasshauer M, Paschke R, Stumvoll M. Adiponectin, obesity, and cardiovascular disease. Biochimie 2004; 86: 779-784.
5. Agarwal AK, Garg A. Congenital generalized lipodystrophy: significance of triglyceride biosynthetic pathways. Trends Endocrinol Metab 2003. 14;214-221.
6. (NHANES) National Health and Nutrition Examination Suvey 1999-2000.
7. Finkelstein EA, Fiebelkorn IC, Wang G. National medical spending attributable to overweight and obesity: How much, and who's paying? Health Affairs 2003; W3: 219-226.
8. Agarwal AK, et al. AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat Genet 2002. 31;21-23.
9. Magre J, et al. Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet 2001. 28;365-370.
10. Agarwal AK, Garg A. Seipin: a mysterious protein. Trends Endocrinol Metab 2004. 10;440-444.
11. Garg A, Fleckenstein JL, Pechock RM, Grundy SM. Peculiar distribution of adipose tissue in patients with congenital generalized lipodystrophy. J Clin Endocrin Metab 1992. 75; 358-361.
12. Simha V, Garg A. Phenotypic heterogeneity in body fat distribution in patients with congenital generalized lipodystrophy caused by mutations in the AGPAT2 or Seipin genes. J Clin Endocrin Metab 2003. 88; 5433-5437.

Previous Research Activities or Publications with Medical Students:

Doris Duke Clinical Research Fellowship (2002-present)
Summer Student Research Fellows

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