Document Type

Dissertation

Degree

Doctor of Philosophy (PhD)

Department

Dietetics and Nutrition

First Advisor's Name

Fatma G. Huffman

First Advisor's Committee Title

Co-Committee Chair

Second Advisor's Name

M. Alejandro Barbieri

Second Advisor's Committee Title

Co-Committee Chair

Third Advisor's Name

Vijaya Narayanan

Third Advisor's Committee Title

Committee member

Fourth Advisor's Name

Juan P. Liuzzi

Fourth Advisor's Committee Title

Committee member

Fifth Advisor's Name

Wensong Wu

Fifth Advisor's Committee Title

Committee member

Keywords

Adipocyte, 3T3-L1, Adipogenesis, Methylglyoxal, Rab5-GEF, RAP6, Endocytosis, Obesity, Diabetes, Cardiovascular Disease, Ethnic Minority

Date of Defense

3-31-2017

Abstract

Internalization and trafficking of ligand-receptor complex rely on a particular set of proteins, e.g. small GTPase protein Rab5 and its activators called guanine nucleotide exchange factors. Rab5-activating protein 6 (RAP6), a Vps9-containing protein, may participate in Rab5-mediated insulin signaling and receptor trafficking. A dicarbonyl compound methylglyoxal was found to alter insulin signaling in preadipocytes. This dissertation aimed to investigate the association of RAP6 activity on 3T3-L1 preadipocyte differentiation and those driven by methylglyoxal. Overexpression of RAP6 inhibited preadipocyte differentiation, Ser473-phosphorylation of Akt1, and expression of adipogenic marker PPARγ, but not C/EBPα. Methylglyoxal (10 µM) increased preadipocyte differentiation, proliferation and expression of PPARγ, C/EBPα and p-Akt1-Ser473, but appeared to be neutralized by RAP6 overexpression. The findings suggest that RAP6 may be a key modulator in regulating the stimulatory effect of methylglyoxal on preadipocyte differentiation. The associations of predominant methylglyoxal-derived adduct, methylglyoxal hydroimidazolone 1 (MGH1), with selected risk factors of chronic diseases in Black participants with and without type 2 diabetes (n=234 controls and n=254 cases) were also investigated. Only in individuals with diabetes, MGH1 levels were positively associated with fasting plasma glucose (B=0.240, p=0.037), homocysteine (B=0.355, p=0.014) and triglyceride (B=0.190, p=0.049). Being African Americans with type 2 diabetes was associated with lower MGH1 levels as compared to being Haitian American with diabetes (B=-0.334, p=0.016). The findings suggest that methylglyoxal may be linked to hyperglycemia and metabolic changes in type 2 diabetes, and may differently impact the development of diabetes across Black subgroups.

Identifier

FIDC001744

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