Circadian Genes and Adipose Function: Impact of Chronotype, Obesity and Race

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DESCRIPTION (provided by applicant): There has been an alarming increase in the prevalence of obesity in the United States, but women, in particular African Americans, have been especially hard it. It is thus crucial to identify novel pathways that mediate the increase prevalence of insulin resistance associated with obesity. Disturbances of the circadian clock system in peripheral tissues have emerged as a putative novel risk factor for weight gain and insulin resistance. While the cross-talk between the circadian system and metabolism has been well-documented in nocturnal animal models, in which, contrary to the human, the active period is aligned with high melatonin levels and elevated neuronal activity in the suprachiasmatic nucleus. The potential role of alterations in peripheral clock function in adipose tissue in promoting adiposity-related insulin resistance in women has not been elucidated. Additionally, bariatric surgery has emerged as a frontline treatment with over 200,000 procedures being performed in the US annually. In an ongoing collaboration with a bariatric surgeon, we have obtained preliminary evidence that bariatric surgery rapidly improves insulin action in primary human adipocytes. The central hypothesis of this application is that the reduction in insulin sensitivity in adipose tissue is mediated by alterations in the circadian expression of clock and metabolic genes, and that these disturbances are more pronounced in obese AA women versus non-Hispanic white (NHW) women. Subcutaneous fat biopsies from obese AA and NHW human volunteers will be collected 2 weeks prior to surgery, as well as from matched lean control women. Circadian gene expression will be measured in cultured adipose tissue over a 24 hr period and compared to the systemic insulin sensitivity and chronotype of each individual. During the week prior to surgery, bedtimes and mealtimes will be standardized for half of the obese subjects to determine the impact of central circadian alignment on peripheral circadian gene expression in subcutaneous and mesenteric fat collected at the start of the bariatric procedure. Finally, surgical patients will return 2 and 12 weeks post-surgery before long term weight loss has occurred and subcutaneous fat biopsies will be collected. At 2 weeks, we will determine if the rapid improvement in insulin sensitivity in adipose tissue is commensurate with improvement in the phase and amplitude of circadian gene expression in NHW and AA women. At 12 weeks, when normal meal schedules have resumed but patients remain obese, we will elucidate if bariatric surgery causes an earlier chronotype, which is associated with protection from the development of metabolic disease. At both time points, we will determine if the decreased long term efficacy of bariatric surgery in AA women is concomitant with a reduction in the restoration of peripheral circadian gene expression in adipose tissue. These studies should provide novel and important insights into the interplay of changes in peripheral circadian gene expression and insulin sensitivity that occurs in obesity in NHW and AA women, and may also lead to novel therapeutic interventions to reverse the current racial disparities in the prevalence of metabolic disease in women.