OBJECTIVE: The purpose of this article was to determine the relationships among total body fat, visceral adipose tissue (VAT), fat cell size (FCS), ectopic fat deposition in liver (intrahepatic lipid (IHL)) and muscle (intramyocellular lipid (IMCL)), and insulin sensitivity index (Si) in healthy overweight, glucose-tolerant subjects and the effects of calorie restriction by diet alone or in conjunction with exercise on these variables. RESEARCH DESIGN AND METHODS: Forty-eight overweight volunteers were randomly assigned to four groups: control (100% of energy requirements), 25% calorie restriction (CR), 12.5% calorie restriction +12.5% energy expenditure through structured exercise (CREX), or 15% weight loss by a low-calorie diet followed by weight maintenance for 6 months (LCD). Weight, percent body fat, VAT, IMCL, IHL, FCS, and Si were assessed at baseline and month 6. RESULTS: At baseline, FCS was related to VAT and IHL (p < 0.05) but not to IMCL. FCS was also the strongest determinant of Si (p < 0.01). Weight loss at month 6 was 1 +/- 1% (control, mean +/- SE), 10 +/- 1% (CR), 10 +/- 1% (CREX), and 14 +/- 1% (LCD). VAT, FCS, percent body fat, and IHL were reduced in the three intervention groups (p < 0.01), but IMCL was unchanged. Si was increased at month 6 (p = 0.05) in the CREX (37 +/- 18%) and LCD (70 +/- 34%) groups (p < 0.05) and tended to increase in the CR group (40 +/- 20%, p = 0.08). Together the improvements in Si were related to loss in weight, fat mass, and VAT, but not IHL, IMCL, or FCS. CONCLUSIONS: Large adipocytes lead to lipid deposition in visceral and hepatic tissues, promoting insulin resistance. Calorie restriction by diet alone or with exercise reverses this trend.
Copyright American Diabetes Association. Reprinted with permission from The American Diabetes Association.

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