Independent influences of central fat and skeletal muscle lipids on insulin sensitivity

Objective: Insulin resistance is closely associated with two disparate aspe cts of lipid storage: the intracellular lipid content of skeletal muscle an d the magnitude of central adipose beds. Our aim was to determine their rel ative contribution to impaired insulin action. Research Methods and Procedures: Eighteen older (56 to 75 years of age) men were studied before elective knee surgery. Insulin sensitivity (M/DeltaI) was determined by hyperinsulinemic-euglycemic clamp. Central abdominal fat (CF) was assessed by DXA. Skeletal muscle was excised at surgery and assaye d for content of metabolically active long-chain acyl-CoA esters (LCAC). Results: Significant inverse relationships were observed between LCAC and M /DeltaI (R-2 = 0.34, p = 0.01) and between CIF and M/DeltaI (R-2 = 0.38, p = 0.006), but not between CF and LCAC (R-2 = 0.0005, p = 0.93). In a multip le regression model (R-2 = 0.71, p < 0.0001), both CF (p = 0.0006) and LCAC (p 0.0009) were independent statistical predictors of M/DeltaI. Leptin lev els correlated inversely with M/DeltaI (R-2 = 0.60, p = 0.0002) and positiv ely with central (R-2 = 0.41, p = 0.006) and total body fat (R-2 = 0.63, p = 0.0001). Discussion: The mechanisms by which altered lipid metabolism in skeletal mu scle influences insulin action may not be related directly to those linking central fat and insulin sensitivity. In particular, it is unlikely that mu scle accumulation of lipids directly derived from labile central fat depots is a principal contributor to peripheral insulin resistance. Instead, our results imply that circulating factors, other than nonesterified fatty acid s or triglyceride, mediate between central fat depots and skeletal muscle t issue. Leptin was not exclusively associated with central fat, but other fa ctors, secreted specifically from central fat cells, could modulate muscle insulin sensitivity.