Abstract
CD44 is a multifunctional membrane receptor implicated in the regulation of several biological processes, including inflammation. CD44 expression is elevated in liver and white adipose tissue (WAT) during obesity suggesting a possible regulatory role for CD44 in metabolic syndrome. To study this hypothesis, we examined the effect of the loss of CD44 expression on the development of various features of metabolic syndrome using CD44 null mice. Our study demonstrates that CD44-deficient mice (CD44KO) exhibit a significantly reduced susceptibility to the development of high fat-diet (HFD)-induced hepatic steatosis, WAT-associated inflammation, and insulin resistance. The decreased expression of genes involved in fatty acid synthesis and transport (Fasn and Cd36), de novo triglyceride synthesis (Mogat1), and triglyceride accumulation (Cidea, Cidec) appears in part responsible for the reduced hepatic lipid accumulation in CD44KO(HFD) mice. In addition, the expression of various inflammatory and cell matrix genes, including several chemokines and its receptors, osteopontin, and several matrix metalloproteinases and collagen genes was greatly diminished in CD44KO(HFD) liver consistent with reduced inflammation and fibrogenesis. In contrast, lipid accumulation was significantly increased in CD44KO(HFD) WAT, whereas inflammation as indicated by the reduced infiltration of macrophages and expression of macrophage marker genes, was significantly diminished in WAT of CD44KO(HFD) mice compared to WT(HFD) mice. CD44KO(HFD) mice remained considerably more insulin sensitive and glucose tolerant than WT(HFD) mice and exhibited lower blood insulin levels. Our study indicates that CD44 plays a critical role in regulating several aspects of metabolic syndrome and may provide a new therapeutic target in the management of insulin resistance.
Highlights
Obesity is a major health-care concern in many Westernized countries
Studies from our own laboratory revealed that CD44 was expressed at significantly higher levels in white adipose tissue (WAT) of wild type (WT) mice fed a high fat diet (HFD) (Fig. 1A) and was elevated in liver of 7 months old mice or mice fed a HFD compared to 2 months old mice
A similar correlation between CD44 expression and obesity was observed in WAT of WT mice and mice deficient in the nuclear receptor TAK1 mice that are resistant to HFD-induced obesity (Figure S1) [23]
Summary
Obesity is a major health-care concern in many Westernized countries. In the United States 30% of the population is considered obese, while more than 66% of adults and almost 17% of children and adolescents are overweight [1,2]. Abnormal accumulation of lipids in the liver has been reported to cause hepatic steatosis and accelerate the progression of insulin resistance [3,4,5]. This is supported by findings showing that deficiencies in a number lipid transport, lipogenic or lipolytic genes promote or inhibit the development of hepatic steatosis and insulin resistance. Increased infiltration of proinflammatory M1 macrophages and other immune cells, including T lymphocytes, in adipose tissue and the subsequent release of proinflammatory cytokines, has been shown to play a critical role in this enhanced inflammatory state [9,10,11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
