The objective of this study is to determine whether middle-aged adults prescribed a low carbohydrate-high fat (LCHF) or low fat (LF) diet would have greater loss of central fat and to determine whether the insulin resistance (IR) affects intervention response. A total of 50 participants (52.3 ± 10.7 years old; 36.6 ± 7.4 kg/m2 BMI; 82% female) were prescribed either a LCHF diet (n = 32, carbohydrate: protein: fat of 5%:30%:65% without calorie restriction), or LF diet (n = 18, 63%:13–23%: 10–25% with calorie restriction of total energy expenditure—500 kcal) for 15 weeks. Central and regional body composition changes from dual-x-ray absorptiometry and serum measures were compared using paired t-tests and ANCOVA with paired contrasts. IR was defined as homeostatic model assessment (HOMA-IR) > 2.6. Compared to the LF group, the LCHF group lost more android (15.6 ± 11.2% vs. 8.3 ± 8.1%, p < 0.01) and visceral fat (18.5 ± 22.2% vs. 5.1 ± 15.8%, p < 0.05). Those with IR lost more android and visceral fat on the LCHF verses LF group (p < 0.05). Therefore, the clinical prescription to a LCHF diet may be an optimal strategy to reduce disease risk in middleaged adults, particularly those with IR.