Research Overview

Energy and metabolic homeostasis are critical for health and survival. Conversely, impaired regulation of these homeostatic processes, particularly in the modern obesogenic environment, leads to substantial morbidity and mortality (i.e., obesity, insulin resistance, overt diabetes, dyslipidemia, etc.).  


Our laboratory focuses on defining the mechanisms by which “fat” contributes to normal metabolism and disease. Most recently, these efforts have focused on understanding 1) intracellular lipid homeostasis and pathways of triacylglycerol hydrolysis (lipolysis), 2) novel adipocyte-secreted factors and their relationship to metabolic disease, and 3) novel genes/loci linked to metabolic diseases in humans. We also conduct clinical trials related to rare lipid and adipose tissue disorders, particularly those that contribute to severe hypertriglyceridemia and insulin resistance.  

The Physiological and Cellular Role of Triacylglycerols and Adipose Tissue

in Energy and Metabolic Homeostasis

Research Area #1 

Intracellular lipid homeostasis  

The ability to synthesize (lipogenesis, lipid synthesis), store, and breakdown/release (lipolysis) energy in the form of triacylglycerols is a fundamental process, not just in adipose tissue, but in all tissues. Our research investigates mechanisms that influence the above processes, as well as their physiological relevance. We have contributed to the understanding of key lipid metabolizing enzymes, ATGL/PNPLA2 and adiponutrin/PNPLA3. The former causes Neutral Lipid Storage Disease with Myopathy (NLSDM) in humans. The latter contains a variant (I148M) that is highly associated with non-alcoholic fatty liver disease in humans. Our goal is to understand how fat is safely stored and metabolized in the body, as well as how/why these processes go awry in disease. 


Research Area #2 

Adipose tissue as an endocrine organ  

Adipose-secreted factors (i.e., adipokines, cytokines, lipokines, etc.) are well known to have diverse metabolic effects and also serve as potential therapeutic targets. Numerous potential factors have been identified in preclinical models (i.e., cells, mice); however, their function and physiological relevance remain poorly understood in humans. To address these issues, we evaluate serum and/or tissue endocrine factors in human subjects who are very well-characterized for metabolic phenotypes in the context of different conditions and/or interventions (i.e., diet, physical activity, pharmacotherapy). In this way, we are able to link scientific findings in preclinical models to normal metabolism and disease in humans and vice versa. We are currently participating in a large multi-institutional study to understand the impact of adipose tissue and adipose-secreted factors on muscle, mobility, and aging. Our goal is to identify novel mechanisms by which adipose tissue contributes to disease-relevant phenotypes, and ultimately, to identify targets for therapeutic intervention. 

Research Area #3 

Identification and characterization of genes/variants that contribute to obesity and metabolic disease in humans 

In the era of genomics and personalized medicine, the number of genetic variants that influence human disease and/or its treatment is increasing exponentially – notably much faster than the corresponding functional characterization of these variants. Obesity is a highly heritable disease (60-80%), and yet less than 3% of this heritability is explained by currently identified genetic variants.  Furthermore, the majority of these variants have been identified in humans of predominantly European ancestry. We are currently participating in a multi-institutional, multi-disciplinary collaboration to identify and characterize novel genetic and environmental risk factors for metabolic disease in Samoans – a population at high risk for metabolic disease that is underrepresented in science. These studies identified a variant in CREBRF (R457Q) that increases the risk of obesity but decreases the risk of diabetes. We have established preclinical models in cells and mice to understand the mechanisms by which this gene/variant (and other genes/variants) contribute to metabolic phenotypes. The goal is to translate this knowledge into better strategies for prevention and treatment of metabolic diseases in humans. 


Research Area #4 

Improving prevention and treatment of dyslipidemias and adiposopathies associated with severe hypertriglyceridemia and/or insulin resistance

Several clinical conditions are characterized as aberrant fat storage/metabolism, leading to too much fat (triacylglycerols) in the blood. This can result from the inability to transfer fatty acids from triacylglycerol-rich lipoproteins (TRLs) into tissues (i.e., lipoprotein lipase deficiency), from the inability of adipose tissue to store fatty acids as triacylglycerols (i.e., lipodystrophy), or from increased lipolysis of triacylglycerols and release of fatty acids into the bloodstream (i.e., obesity, insulin resistance, diabetes). Hypertriglyceremia and adiposopathies increase the risk of cardiovascular disease and acute pancreatitis, both of which are associated with substantial morbidity and mortality. We perform clinical trials to evaluate the efficacy and safety of novel therapies for these conditions. We also conduct additional genetic/genomic and phenotypic evaluations to better inform diagnosis and treatment. Our goal is identify better and more personalized therapies for these disorders.