Background: Among the dietary macronutrients, protein is the most potent in decreasing food intake and potentially body weight.Although the major milk proteins-casein and whey-are reported to decrease intake, little is known oftheir relative efficaeies in improving energy balance and diabetic control.We compared the effects of dietary supplementation with casein or whey on food intake (FI), energy expenditure (EE), body weight (BW), body composition (BC) and glucose tolerance in a diet-induced obese (DIO) rat model.Methods: Obesity was induced in 24 male obesity-prone Sprague Dawley rats by feeding a high-fat diet (calories: 33% fat, 14% egg albumin protein) for 8 weeks (wks).The DIO rats were randomized to 3 isocaloric dietary treatments: 1) control (14% calories egg albumin; CON); 2) casein (40% calories casein; CAS), or 3) whey (40% calories whey protein isolate; WPI) groups and continued for 6 wks.FI and EE were monitored by a CLAMS system, BC recorded by an MRI system, and an intraperitoneal glucose tolerance test was also conducted.Results: The main findings were: 1) Compared to CON, WPI and CAS groups reduced FI during first 10 days (d) by about 18%.On d 2-4, relative to CON, FI was reduced FI by 31-36% with WPI and by 14-17% with CAS.By d 11, no differences in FI were detected among treatments.Importantly, despite a reduction in FI, both the WPI and CAS rats had similar EE as CON rats.This indicates that dietary CAS and WPI may attenuate the reduction in EE that often accompanies reduced FI and thereby likely contribute to BW loss.2) From d 8 onwards, WPI decreased BW by ~11% compared to CON.BC analysis revealed that WPI tended to decrease fat mass (WPI vs.CON; 14% vs.16%, respectively) and increase lean mass (WPI vs.CON; 80% vs 78%, respectively).3) WPI produced a remarkable improvement in the glucose tolerance (25%) compared to CON.Conclusions: High-whey and casein diets decreased food intake and body weight, improved glucose tolerance, and likely enhanced energy expenditure with whey being particularly more effective.