Activating brown adipose tissue (BAT) could have far-reaching health benefits in combating obesity and obesity- related complications. Consumed dietary lipids elevates sympathetic activity and thermogenesis in BAT to counteract the energy surplus. On the other hand, chronic consumption of a high-fat diet (HFD) promotes excess energy intake as well as reduces diet-induced BAT thermogenesis, in part due to decreased BAT sympathetic activity, and contributes to the development of obesity. Apolipoprotein A-IV (ApoA-IV), a well-known satiation protein, is secreted by the small intestine (as much as 3% of the proteins) and the hypothalamus in response to dietary lipids. Our preliminary data indicate that exogenous administration of ApoA-IV can stimulate intracellular lipolysis to generate BAT thermogenesis and may shunt dietary lipids into the BAT for the maintenance of thermogenesis. Because vagal afferents are required for ApoA-IV-induced satiation through neuronal activation in the brain, and the hypothalamus controls BAT activity, ApoA-IV-induced BAT thermogenesis is possibly mediated through the stimulation of brain-BAT neurocircuits. Thus, the action of ApoA- IV on neural system is uniquely involved in the inhibition of food intake as well as the stimulation of BAT thermogenesis. Our central hypothesis is that intraperitoneally administered ApoA-IV can elevate BAT thermogenesis and energy expenditure through the activation of sympathetic outflow to BAT in HFD-induced obese animals.
Specific Aim 1 will test the hypothesis that intraperitoneally administered ApoA-IV elevates BAT thermogenesis through activation of lipolysis and lipid diversion in lean and HFD-induced obese animals. The roles of ApoA-IV in lipolysis and thermogenesis in BAT and lipid diversion into BAT will be examined. Furthermore, we will determine whether chronic administration of ApoA-IV will combat obesity in HFD-fed mice through elevation of energy expenditure and thermogenesis in BAT and beige adipocytes.
Specific Aim 2 will test the hypothesis that intraperitoneally administered ApoA-IV elevates sympathetic activity to BAT. We will determine the involvement of sympathetic innervation of BAT and sympathetic activity important for ApoA-IV- induced BAT thermogenesis. In addition, sympathetic activity in individual organs will also be measured. ApoA- IV's action on the brain and vagal afferent nerve for the stimulation of sympathetic activity will be identified. This project will provide ample and exciting research opportunities to expose undergraduate and graduate students to biomedical research involving dietary intervention, neurophysiology and pharmacological studies. In addition, these students will also learn how to determine metabolic function of HFD-induced obese animals. Successful completion of the proposed research will identify specific mechanism underlying ApoA-IV actions on BAT thermogenesis and energy homeostasis. New therapeutic targets based on these studies could thus be directly translated to therapeutics to improve obesity and obesity-related complications.
Completion of this proposed research will provide new insights regarding how Apolipoprotein A-IV increases thermogenesis in brown adipose tissue through activation of the brain-vagal afferent nerves-BAT neurocircuitry. The action of ApoA-IV on energy homeostasis and lipid diversion may be useful as a therapeutic to combat obesity and type 2 diabetes mellitus in humans.
