Gender Differences in Metabolic Syndrome: the Role of Ccr5

The regional distribution of body fat is a distinct characteristic of sexual differentiation. Women generally develop peripheral adiposity, with preferential gluteal fat accumulation, whereas men are more prone to abdominal and visceral obesity. Obesity-induced chronic, low grade inflammation in white adipose tissue (WAT), especially in visceral WAT is critical in the pathogenesis of insulin resistance syndrome and diabetes. Currently, CCR5 (chemokine C-C motif receptor 5) and its ligands (RANTES) have been identified and demonstrated it could mediate leukocyte infiltration and the inflammatory response in adipose tissue. CCR5 knockout mice are protected from insulin resistance, hepatic steatosis, and diabetes induced by high-fat feeding. This effect of lacking CCR5 in obesity is related to both reduction of total adipose tissue macrophage (ATM) content and impairment of M2-to-M1 ATM polarization. Moreover, one interesting findings is obese males had higher T cell numbers and higher RANTES and CCR5 mRNA expression in adipose tissue than obese females. However, there has been no further research regarding CCR5 and insulin resistance in obese females beyond this report. Hence, we did several pilot studies to address this issue. Our preliminary findings suggest that high-fat diet-induced obesity (DIO) and insulin resistance were significantly protected in CCR5 KO female mice. In contrast, only a slightly protection effects were observed in male CCR5 KO mice. Based on our preliminary findings, we propose that CCR5 plays a critical role in gender differences in protecting against obesity and insulin resistance. If this is the case, there are several questions that need to be addressed. What is the role of CCR5 in gender differences in protecting against high-fat diet-induced obesity and insulin resistance syndrome? Whether CCR5 deficiency protects against insulin resistance syndrome in female obese mice are associated with estrogen. Is androgen related to the less protective effects of CCR5 deficiency in obese male mice? What are the cellular mechanisms of CCR5 in protecting against insulin resistance syndrome in gender differences? To address these questions, we will test the main hypothesis that CCR5 mediates gender differences in progression of obesity and insulin resistance in mice on high-fat diet feedings. To address these hypotheses, we will perform experiments based on the following three specific aims. Specific Aim 1: Determine the role of CCR5 in gender differences in protecting against obesity and insulin resistance syndrome of high-fat diet fed mice. In this aim, we will use genetic CCR5 knockout (KO) strategy to test the role of CCR5 in gender differences and in protecting against obesity and insulin resistance. Specific Aim 2: Delineate the role of estrogen in protecting against obesity and insulin resistance in CCR5 KO female obese mice. We plan to perform the ovariectomy surgery and 17p estradiol replacement in CCR5 KO obese female mice to verify whether estrogen can enhance the protective effects of CCR5 deficiency. Specific Aim 3: Study the role of androgens in obesity and insulin resistance in CCR5 KO male mice. We plan to perform the castration surgery in CCR5 KO obese male mice to verify whether androgen can influence or attenuate the protective effects of CCR5 deficiency in male obese mice. Taking a broad view on sex differences in obesity, insulin resistance, and diabetes provides an opportunity for greater understanding the pathogenesis of disease and as such provides a clear motivation for clinicians to explore how therapies may be tailored to the individual in a sex-dependent way.

Project ID:PC10601-0866
External Project ID:MOST105-2320-B182-039-MY3