We will examine the overarching hypothesis that nocturnal release of FFA from the visceral and possibly subcutaneous compartments, will change FFA delivery to the liver, reduce hepatic insulin clearance, cause hyperinsulinemia, and thus reduce insulin sensitivity in peripheral tissues. I. We will address the importance of the nocturnal surge in FFA in the development of insulin resistance with fat feeding. We predict that visceral fat makes a significant contribution to the nocturnal surge, and that this may account for the intimate link between visceral fat and insulin resistance. 1) We will block the nighttime surge in lipolysis using an Al adenosine receptor partial agonist, reducing sympathetic input to the visceral depot via sympathectomy, and using the pS blocking agent, bupranolol. 2) We shall examine the relationship between sleep states and the nocturnal surge in lipolysis. Animals will be telemetered for continuous EEG measurements in a quiet and isolated environment, and the relationship between sleep, lipolysis (measured using plasma FFA and tracer dilution methods) and neurally active agents, including catecholamines and leptin, will be assessed over 24 hr periods with hourly sampling. II. We will examine the role of nocturnal FFA on changes in insulin clearance by the liver. We will block nocturnal FFA surge to examine whether changes in hepatic clearance can be blocked acutely. Finally, we will chronically block the nocturnal surge of FFA by infusion of lipolytic blocking agents and examine if the reduction in hepatic clearance is altered. We will biopsy liver tissue to detennine the molecular mechanisms underlying alterations in liver insulin clearance (CEACAM 1, insulin degrading enzyme). III. We will examine the hypothesis that changes in liver insulin clearance are central to the development of the insulin resistance in fat feeding, in that they result in hyperinsulinemia as a cause of peripheral insulin resistance. Changes in clearance in the liver will be caused by knockdown of CEACAM1 using the antisense approach, end-to-side portocaval shunt simulate, by chronic insulin infusion, the similar degree of peripheral appearance of insulin which would be caused by the degree of reduction in liver insulin clearance that we observed with elevated fat feeding.
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