Age-related neuronal regulation of thermogenesis and lipid metabolism

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Project Summary Aging is associated with obesity, cardiovascular disease, and type 2 diabetes mellitus. Activating brown adipose tissue (BAT) thermogenesis in humans results in elevation of triglyceride clearance and insulin action, and has great potential to combat obesity, cardiovascular disease, and type 2 diabetes mellitus. We have reported in young adult mice that ACUTE injection of apolipoprotein A-IV(ApoA-IV): 1) elevates thermogenesis and uptake of fatty acid (FA) in BAT and 2) stimulates sympathetic neural activity (SNA) in BAT but reduces SNA in liver of chow-fed mice. However, its effect on lipid metabolism in adipose tissue and liver through alteration of SNA in old mice remains unknown. Chronic consumption of high-fat diet (HFD) suppresses ApoA-IV production normally induced by acute consumption of dietary lipids and attenuates SNA of BAT and thermogenesis. In this regard, we have preliminary evidence in young, HFD-fed mice that CHRONIC infusion of ApoA-IV: 1) elevates thermogenesis in BAT and beige adipose tissue (BeAT) and overall energy expenditure; 2) increases hepatic expression of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), implying restriction of hepatic lipogenesis; and 3) reduces hepatic and plasma lipid content, fat mass, and body weight gain. These findings suggest that chronic infusion of ApoA-IV alters lipid metabolism in BAT, BeAT and liver through neural or CEACAM1-mediated pathways. Because elderly humans and older rodents have a large decline in BAT activity, we theorize that the lower thermogenesis results in impaired lipid oxidation for energy combustion in BAT/BeAT, insufficient FA uptake into these adipose tissues, and elevated lipogenesis and lipid accumulation in the liver. Thus, we propose the innovative hypothesis that increased levels of ApoA-IV will act through sympathetic innervation to elevate lipid oxidation and uptake in BAT/BeAT and through CEACAM1-mediated reduction of lipogenesis in liver, subsequently reducing hepatic and plasma triglyceride (TG) in old, obese animals. This hypothesis will be tested using comprehensive, innovative, well-designed approaches. Aim 1 will investigate ApoA-IV’s role in sympathetic activation of BAT/BeAT to reverse age-attenuated thermogenesis. Aim 2 will investigate ApoA-IV’s effects on BAT/BeAT and hepatic lipid metabolism through neural or CEACAM1- mediated pathways to lower hepatic and plasma triglycerides. A major strength of this proposal is the interdisciplinary collaboration between Drs. Chunmin Lo (lipid metabolism & neurophysiology) and Haifei Shi (neuroendocrine & adipose biology) with support from Drs. Sonia Najjar (aging & CEACAM1-meidated insulin action), Darlene Berryman (aging & hormones) and Karen Coschigano (molecular biology & signaling pathways). As demonstrated by the strong preliminary data, these investigators have productively collaborated and will delineate the novel mechanism of ApoA-IV in downregulation of age-related obesity and plasma triglycerides, leading to treatments against this health problem in elderly humans.