Interdisciplinary Graduate Program
Program in Molecular Medicine
First Thesis Advisor
Michael P. Czech, PhD
Brown Adipocytes, Brown Adipose Tissue, Glucose Intolerance, Lipid Droplets, Hepatocytes
Dissertations, UMMS; Adipocytes, Brown; Adipose Tissue, Brown; Glucose Intolerance; Lipid Droplets; Hepatocytes
Chronic exposure of humans or rodents to high calorie diets leads to hypertriglyceridemia and ectopic lipid deposition throughout the body, resulting in metabolic disease. Cellular lipids are stored in organelles termed lipid droplets (LDs) that are regulated by tissue-specific LD proteins. These proteins are critical for lipid homeostasis, as humans with LD protein mutations manifest metabolic dysfunction. Identification of novel components of the LD machinery could shed light on human disease mechanisms and suggest potential therapeutics for Type 2 Diabetes.
Microarray analyses pinpointed the largely unstudied Hypoxia-Inducible Gene 2 (Hig2) as a gene that was highly expressed in obese human adipocytes. Imaging studies demonstrated that Hig2 localized to LDs in mouse hepatocytes and the human SGBS adipocyte cell line. Thus, this work examined the role of Hig2 as a LD protein in liver and adipose tissue.
Hig2 deficiency reduced triglyceride deposition in hepatocytes; conversely, ectopic Hig2 expression promoted lipid deposition. Furthermore, liver-specific Hig2-deficient mice displayed improved glucose tolerance and reduced liver triglyceride content. Hig2 deficiency increased lipolysis and -oxidation, accounting for the reduced triglyceride accumulation.
Similarly, adipocyte-specific Hig2-deficient mice displayed improved glucose tolerance, reduced adipose tissue weight and brown adipose tissue that was largely cleared of lipids. These improvements were abrogated when the animals were placed in thermoneutral housing and brown adipocyte-specific Hig2-deficient mice also displayed improved glucose tolerance, suggesting that active brown fat largely mediates the metabolic phenotype of Hig2 deletion. Thus, this work demonstrates that Hig2 localizes to LDs in liver and adipose tissue and promotes glucose intolerance.
DiStefano, MT. A Role for the Lipid Droplet Protein HIG2 in Promoting Lipid Deposition in Liver and Adipose Tissue: A Dissertation. (2016). University of Massachusetts Medical School. GSBS Dissertations and Theses. Paper 830. DOI: 10.13028/M2Q59S. https://escholarship.umassmed.edu/gsbs_diss/830
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