It has been suggested that a genetic predisposition and an increased total fat mass, particularly a specific increase in visceral fat, contribute to the metabolic aberrations associated with human non-insulin-dependent diabetes mellitus (NIDDM). In this study, we investigated the interactions between genetic and dietary components on fat distribution and metabolism in two mouse strains, one genetically predisposed to NIDDM (BL/6) and one not (A/J), fed either a chow diet or a high-fat, high-simple carbohydrate (HFHSC) diet for 5 months. As expected, both strains of mice fed a HFHSC diet were heavier, had more fat in both the subcutaneous (inguinal [ING] and visceral (mesenteric [MES]) regions, and had larger fat cells and higher lipoprotein lipase (LPL) activities. The results of interactions between strain and diet showed important differences in fat distribution and metabolism between strains. In comparison with A/J mice, BL/6 mice fed a HFHSC diet developed hyperglycemia, hyperinsulinemia, and hypercholesterolemia, were heavier, had more overall fat, and particularly increased their MES adipose tissue. This increase in visceral fat mass was due to an increase in fat cell number. In contrast, BL/6 mice fed a chow diet had less overall fat, a smaller MES fat pad with smaller adipocytes, and lower LPL activity than A/J controls. Significant differences between BL/6 and A/J mice fed either a HFHSC or a chow diet were not observed in ING adipose tissue. These data suggest that in BL/6 mice, changes in the metabolic characteristics of visceral fat seem to be a specific characteristic associated with the genetic predisposition for NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)