Obesity-associated extracellular and ultrastructural changes in adipocytes: Impact on insulin sensitivity

Abstract

Obesity is characterized by adipose tissue expansion due to excess caloric intake, which then leads to increased risk for the development of metabolic complications, such as Type 2 diabetes. Obesity-associated changes in adipose tissue include changes in the extracellular matrix of adipocytes, ultrastructural changes within adipocytes, altered adipokine secretion, and altered energy homeostasis.;Adipocytes are embedded in a unique extracellular environment, which undergoes remodeling during adipose tissue expansion to accommodate adipocyte growth. I demonstrate an overall upregulation of extracellular matrix components in adipose tissue during metabolic dysregulation, suggesting a state of "adipose tissue fibrosis" during obesity. I focused on collagen VI, a prominent constituent of the adipose tissue matrix. Using an obese collagen VI null model, I found that in the absence of extracellular collagen VI, adipocytes become hypertrophic and are paradoxically associated with substantial metabolic improvements, including improved glucose and lipid clearance, and a significant reduction in inflammation. Our data highlights the concept of the adipocyte extracellular matrix as a restrictive environment which hinders adipocyte expansion. Therefore, a weakened adipocyte extracellular scaffold enables "stress-free" adipocyte expansion during states of positive energy balance, and is consequently associated with an improved inflammatory and metabolic profile.;Adipocytes are also a major storage center of cholesterol and are enriched in caveolae. This makes them very sensitive to changes in cholesterol levels, such as through the cholesterol-lowering drugs statins. I explored the in vivo effects of statins and find that statins disrupt caveolar invagination in adipocytes. Statins also affect the secretory profile of adipocytes, specifically reducing secretion of the high molecular weight (HMW) form of adiponectin (an insulin-sensitizing adipokine). Surprisingly, this HMW adiponectin secretion defect does not affect insulin sensitivity. Statin exposure also reduces adiposity and adipocyte size in ob/ob mice, suggesting that inhibition of cholesterol biosynthesis can also have implications in triglyceride metabolism in adipocytes.;Our results suggest that both the extracellular matrix and cholesterol can have implications in regulating the degree of adipocyte hypertrophy and makes their study important for understanding obesity and its associated metabolic phenotype.