The accumulation of triglyceride in and around the myocardium of moderately obese individuals is significant, and it is related to FFA exposure, generalized ectopic fat excess, and peripheral vascular resistance. These changes precede LV overload and hypertrophy.

The liver responds to a 6-wk period of calorie restriction with a parallel reduction in lipid uptake and storage, accompanied by enhancement of hepatic insulin sensitivity and clearance.

Iozzo P. The lowering of hepatic fatty acid uptake improves liver function and insulin sensitivity without affecting hepatic fat content in humans. Am J Physiol Endocrinol Metab 295: E413-E419, 2008. First published May 27, 2008 doi:10.1152/ajpendo.00744.2007.-Lipolysis may regulate liver free fatty acid (FFA) uptake and triglyceride accumulation; both are potential causes of insulin resistance and liver damage. We evaluated whether 1) systemic FFA release is the major determinant of liver FFA uptake in fasting humans in vivo and 2) the beneficial metabolic effects of FFA lowering can be explained by a reduction in liver triglyceride content. Sixteen healthy subjects were subdivided in two groups of similar characteristics to undergo positron emission tomography with [11 C]acetate and [ 11 C]palmitate to quantify liver FFA metabolism (n ϭ 8), or magnetic resonance spectroscopy (MRS) to measure hepatic fat content (n ϭ 8), before and after the acute lowering of circulating FFAs by using the antilipolytic agent acipimox. MRS was again repeated after a 1-wk treatment period. Acipimox suppressed FFA levels while stimulating hepatic fractional extraction of FFAs (P Ͻ 0.05). As a result, fasting liver FFA uptake was decreased by 79% (P ϭ 0.0002) in tight association with lipolysis (r ϭ 0.996, P Ͻ 0.0001). The 1-wk treatment induced a significant improvement in systemic (ϩ30%) and liver (ϩ70%) insulin sensitivity (P Ͻ 0.05) and decreased circulating triglycerides (Ϫ20%, P ϭ 0.06) and liver enzymes (ALT Ϫ20%, P ϭ 0.03). No change in liver fat content was observed after either acute or sustained FFA suppression. We conclude that acute and sustained inhibitions of lipolysis and liver FFA uptake fail to deplete liver fat in healthy human subjects. Liver FFA uptake was decreased in proportion to FFA delivery. As a consequence, liver and systemic insulin sensitivity were improved, together with liver function, independently of changes in hepatic triglyceride accumulation. lipolysis; liver metabolism; positron emission tomography; magnetic resonance; acipimox; insulin resistance ACCORDING TO THE OVERFLOW HYPOTHESIS, the provision of fatty acids, as released from adipose tissue to the liver, is responsible for the regulation of liver fat accumulation via hepatic fatty acid uptake (7,14). In turn, liver fat content is proportional to indicators of liver damage such as liver enzymes, suggesting a cause-effect relationship (7,9,14,32). This view implicates that substrate delivery from the circulation plays a dominant, and the intrinsic organ response has a minor, role in the regulation of liver fatty acid uptake. This passive response of the liver remains to be proven in humans in vivo.Lipolysis is not the only source of fatty acids. Lipodystrophy represents an unphysiological state associated with liver steatosis in which endogenous fatty acids may be one major source of triglyceride precursors (25, 27). However, in the normal situation, the meal provides nutrients, suppressing their endogenous release during a time in which hi...