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Chronic dietary protein-restriction can create essential amino acid deficiencies and induce metabolic adaptation through the hepatic FGF21 pathway which serves to maintain host fitness during prolonged states of nutritional imbalance. Similarly, the gut microbiome undergoes metabolic adaptations when dietary nutrients are added or withdrawn. Here we confirm previous reports that dietary protein-restriction triggers the hepatic FGF21 adaptive metabolic pathway and further demonstrate that this response is mediated by the gut microbiome and can be tuned through dietary supplementation of fibers that alter the gut microbiome. In the absence of a gut microbiome, we discover that FGF21 is de-sensitized to the effect of protein-restriction. These data suggest that host-intrinsic adaptive pathways to chronic dietary protein-restriction, such as the hepatic FGF21 pathway, may in-fact be responding first to adaptive metabolic changes in the gut microbiome.

Dietary protein provides essential amino acids (EAAs) for the synthesis of new proteins plus an array of other metabolic functions; many of these functions are sensitive to postprandial plasma and intracellular amino acid concentrations. Recent research has focused on amino acids as metabolic signals that influence the rate of protein synthesis, inflammation responses, mitochondrial activity, and satiety, exerting their influence through signaling systems including mammalian/mechanistic target of rapamycin complex 1 (mTORC1), general control nonrepressed 2 (GCN2), glucagon-like peptide 1 (GLP-1), peptide YY (PYY), serotonin, and insulin. These signals represent meal-based responses to dietary protein. The best characterized of these signals is the leucine-induced activation of mTORC1, which leads to the stimulation of skeletal muscle protein synthesis after ingestion of a meal that contains protein. The response of this metabolic pathway to dietary protein (i.e., meal threshold) declines with advancing age or reduced physical activity. Current dietary recommendations for protein are focused on total daily intake of 0.8 g/kg body weight, but new research suggests daily needs for older adults of ≥1.0 g/kg and identifies anabolic and metabolic benefits to consuming at least 20-30 g protein at a given meal. Resistance exercise appears to increase the efficiency of EAA use for muscle anabolism and to lower the meal threshold for stimulation of protein synthesis. Applying this information to a typical 3-meal-a-day dietary plan results in protein intakes that are well within the guidelines of the Dietary Reference Intakes for acceptable macronutrient intakes. The meal threshold concept for dietary protein emphasizes a need for redistribution of dietary protein for optimum metabolic health.

The dietary reference intakes (DRIs) established an acceptable macronutrient distribution range (AMDR); however, few studies have evaluated differences in metabolic regulations across the DRI range. This study examined differences in glycemic regulations associated with specific ratios of carbohydrate and protein. Male rats (~200 g) were fed either a high-carbohydrate diet (CHO group: 60% of energy as carbohydrates, 12% protein, 28% fat) or a reduced-carbohydrate diet [PRO (protein) group: 42% carbohydrates, 30% protein, 28% fat]. Rats consumed 3 meals/d with energy distributed as 16, 42, and 42%. On d 25, blood and tissues were obtained after 12 h of food deprivation and at 30 and 90 min after the first meal. Before the meal, the CHO group had lower plasma glucose and insulin, reduced liver glycogen, lower expression of hepatic phosphoenolpyruvate carboxylase (PEPCK), and increased fatty acid synthase (FAS) in adipose tissue. After the meal, the CHO group had greater increases in plasma glucose and insulin, producing increased skeletal muscle phosphatidylinositol 3-kinase (PI3-kinase) activity, glucose uptake, and glycogen content, and increased adipose PI3-kinase activity, glucose uptake, and FAS. In contrast, the PRO group had limited postprandial changes in plasma glucose and insulin with reduced muscle PI3-kinase activity and glucose uptake, and no postprandial changes in adipose PI3-kinase activity or FAS. This study demonstrates that changes in carbohydrate and protein intakes within the AMDR produce fundamental shifts in glycemic regulation from high-CHO diets that require insulin-mediated peripheral glucose disposal to high-PRO diets that increase hepatic regulation of glucose appearance into the blood. KEY WORDS: * insulin * fatty acidsynthesis * gluconeogenesis

High-performance physical activity and postexercise recovery lead to significant changes in amino acid and protein metabolism in skeletal muscle. Central to these changes is an increase in the metabolism of the BCAA leucine. During exercise, muscle protein synthesis decreases together with a net increase in protein degradation and stimulation of BCAA oxidation. The decrease in protein synthesis is associated with inhibition of translation initiation factors 4E and 4G and ribosomal protein S6 under regulatory controls of intracellular insulin signaling and leucine concentrations. BCAA oxidation increases through activation of the branched-chain [alpha]-keto acid dehydrogenase (BCKDH). BCKDH activity increases with exercise, reducing plasma and intracellular leucine concentrations. After exercise, recovery of muscle protein synthesis requires dietary protein or BCAA to increase tissue levels of leucine in order to release the inhibition of the initiation factor 4 complex through activation of the protein kinase mammalian target of rapamycin (mTOR). Leucine's effect on mTOR is synergistic with insulin via the phosphoinositol 3-kinase signaling pathway. Together, insulin and leucine allow skeletal muscle to coordinate protein synthesis with physiological state and dietary intake. KEY WORDS: * insulin * mTOR * leucine * muscle * exercise

Diets with total protein intake >1.5 g x kg [sup.1] x [d.sup.1] and carbohydrate intake KEY WORDS: * diabetes * glycemic control * insulin * protein synthesis

This study examined the interaction of 2 diets (high protein, reduced carbohydrates vs. low protein, high carbohydrates) with exercise on body composition and blood lipids in women (n = 48, ~46 y old, BMI = 33 kg/[m.sup.2]) during weight loss. The study was a 4-mo weight loss trial using a 2 x 2 block design (Diet x Exercise). Diets were equal in total energy (7.1 M J/d) and lipids (~30% energy intake) but differed in protein content and the ratio of carbohydrate:protein at 1.6 g/(kg * d) and 3.5 (CHO group), respectively. Exercise comparisons were lifestyle activity (control) vs. a supervised exercise program (EX: 5 d/wk walking and 2 d/wk resistance training). Subjects in the PRO and PRO [+ or -] EX groups lost more total weight and fat mass and tended to lose less lean mass (P = 0.10) than the CHO and CHO [+ or -] EX groups. Exercise increased loss of body fat and preserved lean mass. The combined effects of diet and exercise were additive for improving body composition. Serum lipid profiles improved in all groups, but changes varied among diet treatments. Subjects in the CHO groups had larger reductions in total cholesterol and LDL cholesterol, whereas subjects in the PRO groups had greater reductions in triacylglycerol and maintained higher concentrations of HDL cholesterol. This study demonstrated that a diet with higher protein and reduced carbohydrates combined with exercise additively improved body composition during weight loss, whereas the effects on blood lipids differed between diet treatments. J. Nutr. 135: 1903-1910, 2005. KEY WORDS: * obesity * low-carbohydrate diets * blood lipids * insulin * adiponectin

Leucine (Leu) is known to stimulate translation initiation of protein synthesis at mammalian target of rapamycin (mTOR) in the insulin signaling pathway. However, potential feedback from mTOR to upstream aspects of the insulin signaling pathway remains controversial. This study evaluates the impact of a physiological oral dose of Leu and/or carbohydrate (CHO) on upstream elements of the insulin signaling pathway using phosphatidylinositol 3-kinase (PI 3-kinase) activity and glucose uptake as markers for insulin sensitivity and glucose homeostasis. Rats (~200 g) were fasted 12 h and administered oral doses of CHO (1.31 g glucose, 1.31 g sucrose), Leu (270 rag), or CHO plus Leu. Animals were killed at 15, 30, 60, and 90 min after treatment. Plasma and gastrocnemius muscles were collected for analyses. Treatments were designed to produce elevated blood glucose and insulin with basal levels of Leu (CHO): elevated Leu with basal levels of glucose and insulin (Leu); or a combined increase of glucose, insulin, and Leu (CHO + Leu). The CHO treatment stimulated PI 3-kinase activity and glucose uptake with no effect on the downstream translation initiation factor eIF4E. Leu alone stimulated the release of the translation initiation factor eIF4E from 4E-BP1 with no effects on PI 3-kinase activity or glucose uptake. The CHO + Leu treatment reduced the magnitude and duration of the PI 3-kinase response but maintained glucose uptake similar to the CHO treatment and eIF4E levels similar to the Leu treatment. These findings demonstrate that Leu reduces insulin-stimulated PI 3-kinase activity while increasing downstream translation initiation and with no effect on net glucose transport in skeletal muscle. glucose; insulin receptor substrate-1; initiation factors; phosphatidyl-inositol 3-kinase

Diets with higher protein (1.5 g x [kg.sup.-1] x [d.sup.1]) and reduced carbohydrates (120 to 200 g/d) appear to enhance weight loss due to a higher loss of body fat and reduced loss of lean body mass. While studies of prolonged use of moderate protein diets are not available, short-term studies report beneficial effects associated with increased satiety, increased thermogenesis, sparing of muscle protein loss, and enhanced glycemic control. Combined impacts of a moderate protein diet are likely derived from lower carbohydrates resulting in lower postprandial increase in blood glucose and lower insulin response, and higher protein providing increased BCAA leucine levels and gluconeogenic substrates. A key element in the diet appears to be the higher intake of BCAA leucine with unique regulatory actions on muscle protein synthesis, modulation of the insulin signal, and sparing of glucose use by stimulation of the glucose-alanine cycle. This review focuses on the contributions of leucine and the BCAA to regulation of muscle protein synthesis and glycemic control. KEY WORDS: * obesity * insulin * leucine * BCAA

Amino acids interact with glucose metabolism both as carbon substrates and by recycling glucose carbon via alanine and glutamine; however, the effect of protein intake on glucose homeostasis during weight loss remains unknown. This study tests the hypothesis that a moderate increase in dietary protein with a corresponding reduction of carbohydrates (CHO) stabilizes fasting and postprandial blood glucose and insulin during weight loss. Adult women (n = 24; >15% above ideal body weight) were assigned to either a Protein Group [protein: 1.6 g/(kg * d); CHO 55%]. Diets were equal in energy (7100 kJ/d) and fat (50 g/d). After 10 wk, the Protein Group lost 7.53 [+ or -] 1.44 kg and the CHO Group lost 6.96 [+ or -] 1.36 kg. Plasma amino acids, glucose and insulin were determined after a 12-h fast and 2 h after a 1.67 MJ test meal containing either 39 g CHO, 33 g protein and 13 g fat (Protein Group) or 57 g CHO, 12 g protein and 14 g fat (CHO Group). After 10 wk, subjects in the CHO Group had lower fasting (4.34 [+ or -] 0.10 vs 4.89 [+ or -] 0.11 retool/L) and postprandial blood glucose (3.77 [+ or -] 0.14 vs. 4.33 [+ or -] 0.15 mmol/L) and an elevated insulin response to meals (207 [+ or -] 21 vs. 75 [+ or -] 18 pmol/L). This study demonstrates that consumption of a diet with increased protein and a reduced CHO/protein ratio stabilizes blood glucose during nonabsorptive periods and reduces the postprandial insulin response. KEY WORDS: * insulin * amino acids * leucine *obesity * syndrome X

Claims about the merits or risks of carbohydrate (CHO) vs. protein for weight loss diets are extensive, yet the ideal ratio of dietary carbohydrate to protein for adult health and weight management remains unknown. This study examined the efficacy of two weight loss diets with modified CHO/protein ratios to change body composition and blood lipids in adult women. Women (n = 24; 45 to 56 y old) with body mass indices >26 kg/[m.sup.2] were assigned to either a CHO Group consuming a diet with a CHO/protein ratio of 3.5 (68 g protein/d) or a Protein Group with a ratio of 1.4 (125 g protein/d). Diets were isoenergetic, providing 7100 k J/d, and similar amounts of fat (~50 g/d). After consuming the diets for 10 wk, the CHO Group lost 6.96 [+ or -] 1.36 kg body weight and the Protein Group lost 7.53 [+ or -] 1.44 kg. Weight loss in the Protein Group was partitioned to a significantly higher loss of fat/lean (6.3 [+ or -] 1.2 g/g) compared with the CHO Group (3.8 [+ or -] 0.9). Both groups had significant reductions in serum cholesterol (~10%), whereas the Protein Group also had significant reductions in triacylglycerols (TAG) (21%) and the ratio of TAG/HDL cholesterol (23%). Women in the CHO Group had higher insulin responses to meals and postprandial hypoglycemia, whereas women in the Protein Group reported greater satiety. This study demonstrates that increasing the proportion of protein to carbohydrate in the diet of adult women has positive effects on body composition, blood lipids, glucose homeostasis and satiety during weight loss. KEY WORDS: * obesity * body fat * blood lipids * insulin

Debate about the optimum balance of macronutrients for adult weight maintenance or weight loss continues to expand. Often this debate centers on the relative merits or risks of carbohydrates vs. fats; however, there is increasing interest in the optimal level of dietary protein for weight loss. Diets with a reduced ratio of carbohydrates/protein are reported to be beneficial for weight loss, although diet studies appear to lack a fundamental hypothesis to support higher protein intakes. Presently, needs for dietary proteins are established by the recommended daily allowance (RDA) as the minimum level of protein necessary to maintain nitrogen balance. The RDA define the primary use of amino acids as substrates for synthesis of body proteins. There is emerging evidence that additional metabolic roles for some amino acids require plasma and intracellular levels above minimum needs for protein synthesis. The branched-chain amino acid leucine is an example of an amino acid with numerous metabolic roles that function in proportion with cellular concentration. This review provides an overview of the current understanding of metabolic roles of leucine and proposes a metabolic framework to evaluate the merits of a higher protein diet for weight loss. KEY WORDS: * obesity * weight management * diabetes * protein * leucine * insulin

This study was designed to determine the ability of leucine to enhance muscle recovery after exercise. Male rats (200 g) were divided into five groups: sedentary, food-deprived (SF); exercised, food-deprived (EF); exercised, fed a carbohydrate meal (EC); exercised, fed a leucine meal (EL); and exercised, fed a combination of carbohydrate and leucine (ECL). All meals were administered by oral gavage immediately following exercise. EC and ECL meals were isocaloric and provided 15% of daily energy intake. EL and ECL meals each provided 270 mg leucine. Rats ran on a motor-driven treadmill for 2 h at 36 m/min and were killed 1 h postexercise. Plasma glucose and insulin were measured, and the gastrocnemius and plantaris muscles were excised as a unit to determine glycogen levels and the fractional rate of skeletal muscle protein synthesis ([K.sub.s]). Exercise did not alter plasma glucose or insulin. In contrast, prolonged exercise reduced muscle glycogen (-51%) and [K.sub.s] (-18%). Refeeding a combination of carbohydrate and leucine increased plasma insulin relative to the EF and SF groups and produced complete recovery of muscle [K.sub.s] and glycogen to values not different from those in SF rats. Feeding leucine alone restored [K.sub.s] to that in the SF group without affecting plasma glucose or insulin concentrations. Feeding carbohydrate alone enhanced the rate of glycogen repletion compared to the EF group, concomitant with increases in plasma glucose and insulin. The degree of glycogen recovery correlated with plasma insulin concentrations (r = 0.58, P < 0.05). These data suggest that leucine stimulates muscle protein synthesis following exercise, independent of increased plasma insulin. This is the first demonstration that orally administered leucine stimulates recovery of skeletal muscle protein synthesis after exercise. KEY WORDS: leucine; protein synthesis; glycogen; exercise; rats

This study was designed to determine metabolic and physical performance responses to ingestion of pre-exercise meals with different macronutrient and fiber profiles. Twelve physically active subjects (6 males and 6 females) were used to investigate the metabolic and physical performance consequences of consuming pre-exercise meals consisting of oat, corn, or wheat cereals. A fasting trial served as the control, and all subjects received each treatment in a Latin-square design. Blood samples were drawn before and 85 min after meal ingestion, during 90 min of cycling exercise (60% [Mathematical Expression Omitted]), after a 6.4 km performance ride, and during 60 min of recovery. Expired air samples were collected to determine nutrient utilization. Resting carbohydrate oxidation rates and plasma insulin concentrations after oat ingestion were less than after wheat, and corn and wheat ingestion, respectively (P < 0.05). During exercise, the change in plasma glucose from pre-exercise was greater after consuming wheat and corn compared with oat (P < 0.05), and it was inversely related to pre-exercise plasma insulin concentration (r = -0.55, P = 0.0001). Plasma free fatty acid concentrations were inversely related to plasma lactate concentrations (r = -0.58, P = 0.0001). Free fatty acid concentrations and fat oxidation were greater in fasting trials than all others, but performance ride times did not differ among treatments. Plasma branched-chain amino acid concentrations resembled their respective meal profiles throughout exercise, the performance ride, and recovery. These results indicate that pre-exercise meal composition can influence glucose homeostasis during early exercise and plasma branched-chain amino acid concentrations over a substantial range of metabolic demands. J. Nutr. 126: 1372-1381, 1996. INDEXING KEY WORDS: * humans * pre-exercise feeding * performance * metabolism * amino acids

Abstract Background Leucine (Leu) regulates muscle protein synthesis (MPS) producing dose-dependent plasma Leu and MPS responses from free amino acid solutions. This study examined the role of Leu content from dietary proteins in regulation of MPS after complete meals. Methods Experiment 1 examined 4 protein sources (wheat, soy, egg, and whey) with different Leu concentrations (6.8, 8.0, 8.8, and 10.9% (w/w), respectively) on the potential to increase plasma Leu, activate translation factors, and stimulate MPS. Male rats (~250 g) were trained for 14 day to eat 3 meals/day consisting of 16/54/30% of energy from protein, carbohydrates and fats. Rats were killed on d14 either before or 90 min after consuming a 4 g breakfast meal. Experiment 2 compared feeding wheat, whey, and wheat + Leu to determine if supplementing the Leu content of the wheat meal would yield similar anabolic responses as whey. Results In Experiment 1, only whey and egg groups increased post-prandial plasma Leu and stimulated MPS above food-deprived controls. Likewise, greater phosphorylation of p70 S6 kinase 1 (S6K1) and 4E binding protein-1 (4E-BP1) occurred in whey and egg groups versus wheat and soy groups. Experiment 2 demonstrated that supplementing wheat with Leu to equalize the Leu content of the meal also equalized the rates of MPS. Conclusion These findings demonstrate that Leu content is a critical factor for evaluating the quantity and quality of proteins necessary at a meal for stimulation of MPS.

Abstract Limited data on sex differences in body composition changes in response to higher protein diets (PRO) compared to higher carbohydrate diets (CARB) suggest that a PRO diet helps preserve lean mass (LM) in women more so than in men. Objective To compare male and female body composition responses to weight loss diets differing in macronutrient content. Design Twelve month randomized clinical trial with 4mo of weight loss and 8mo weight maintenance. Subjects Overweight (N = 130; 58 male (M), 72 female (F); BMI = 32.5 ± 0.5 kg/m2) middle-aged subjects were randomized to energy-restricted (deficit ~500 kcal/d) diets providing protein at 1.6 g.kg-1.d-1 (PRO) or 0.8 g.kg-1.d-1 (CARB). LM and fat mass (FM) were measured using dual X-ray absorptiometry. Body composition outcomes were tested in a repeated measures ANOVA controlling for sex, diet, time and their two- and three-way interactions at 0, 4, 8 and 12mo. Results When expressed as percent change from baseline, males and females lost similar amounts of weight at 12mo (M:-11.2 ± 7.1 %, F:-9.9 ± 6.0 %), as did diet groups (PRO:-10.7 ± 6.8 %, CARB:-10.1 ± 6.2 %), with no interaction of gender and diet. A similar pattern emerged for fat mass and lean mass, however percent body fat was significantly influenced by both gender (M:-18.0 ± 12.8 %, F:-7.3 ± 8.1 %, p Conclusion PRO was more effective in reducing percent body fat vs. CARB over 12mo weight loss and maintenance. Men lost percent total body fat and trunk fat more effectively than women. No interactive effects of protein intake and gender are evident.

Abstract Background The Dietary Reference Intakes (DRI) established acceptable macronutrient distribution ranges (AMDR) for carbohydrates and protein, however little is known about differences in glycemic regulations and metabolic signaling across this range. This study examined metabolic outcomes associated with intake of two diets differing in carbohydrate:protein ratios representing the upper and lower ends of the AMDR. Methods Adult, male rats were fed either a high carbohydrate (CHO) diet (60% of energy from carbohydrates, 12% protein, 28% fat; n = 30) or a high protein (PRO) diet (35% carbohydrate, 35% protein, 30% fat; n = 30). Rats were meal-fed 3x/d the respective diets for 10 d and then terminated after overnight food deprivation or 30, 60, 90, 120 min post-prandial (PP). Plasma was collected at each of these points to provide a time course for glucose, insulin and C-peptide. Skeletal muscle and adipose tissues were collected at 0, 30 and 90 min for measurements of basal, early and delayed activation of Akt, p70S6K and Erk 1/2. Data were analyzed by two-way ANOVA. Results The CHO group produced a consistently elevated response in plasma glucose, insulin and C-peptide following the meal through the 120 min time course. In addition, Akt and Erk 1/2 activation in adipose was much higher than in skeletal muscle. Conversely, the PRO group PP glucose response was minimal and insulin maintained a response similar to a biphasic pattern. Tissue responses for the PRO group were greater for Akt and p70S6K signaling in skeletal muscle compared with adipose. Conclusion Taken together these data suggest that altering CHO:PRO ratios within the AMDR produce different glycemic response patterns accompanied by differential metabolic signaling in skeletal muscle and adipose.

Abstract Breast cancer is the most prevalent cancer in American women. Dietary factors are thought to have a strong influence on breast cancer incidence. This study utilized a meal-feeding protocol with female Sprague-Dawley rats to evaluate effects of two ratios of carbohydrate:protein on promotion and early progression of breast tissue carcinomas. Mammary tumors were induced by N-methyl-N-nitrosourea (MNU) at 52 d of age. Post-induction, animals were assigned to consume either a low protein high carbohydrate diet (LPHC; 15% and 60% of energy, respectively) or a high protein moderate carbohydrate diet (HPMC; 35% and 40% of energy, respectively) for 10 wk. Animals were fed 3 meals/day to mimic human absorption and metabolism patterns. The rate of palpable tumor incidence was reduced in HPMC relative to LPHC (12.9 ± 1.4%/wk vs. 18.2 ± 1.3%/wk). At 3 wk, post-prandial serum insulin was larger in the LPHC relative to HPMC (+136.4 ± 33.1 pmol/L vs. +38.1 ± 23.4 pmol/L), while at 10 wk there was a trend for post-prandial IGF-I to be increased in HPMC (P = 0.055). There were no differences in tumor latency, tumor surface area, or cumulative tumor mass between diet groups. The present study provides evidence that reducing the dietary carbohydrate:protein ratio attenuates the development of mammary tumors. These findings are consistent with reduced post-prandial insulin release potentially diminishing the proliferative environment required for breast cancer tumors to progress.

Abstract Dietary Guidelines for Americans provide nutrition advice aimed at promoting healthy dietary choices for life-long health and reducing risk of chronic diseases. With the advancing age of the population, the 2010 Dietary Guidelines confront increasing risks for age-related problems of obesity, osteoporosis, type 2 diabetes, Metabolic Syndrome, heart disease, and sarcopenia. New research demonstrates that the meal distribution and amount of protein are important in maintaining body composition, bone health and glucose homeostasis. This editorial reviews the benefits of dietary protein for adult health, addresses omissions in current nutrition guidelines, and offers concepts for improving the Dietary Guidelines.

Abstract Background To evaluate the metabolic effects of two weight loss diets differing in macronutrient composition on features of dyslipidemia and post-prandial insulin (INS) response to a meal challenge in overweight/obese individuals. Methods This study was a parallel-arm randomized 4 mo weight loss trial. Adults (n = 50, 47 ± 7 y) matched on BMI (33.6 ± 0.6 kg/m2, P = 0.79) consumed energy restricted diets (deficit ~500 kcal/d): PRO (1.6 g.kg-1.d-1 protein and < 170 g/d carbohydrate) or CHO (0.8 g.kg-1.d-1 protein and > 220 g/d carbohydrate) for 4 mos. Meal challenges of respective diets were utilized for determination of blood lipids and post-prandial INS and glucose response at the beginning and end of the study. Results There was a trend for PRO to lose more weight (-9.1% vs. -7.3%, P = 0.07) with a significant reduction in percent fat mass compared to CHO (-8.7% vs. -5.7%; P = 0.03). PRO also favored reductions in triacylglycerol (-34% vs. -14%; P < 0.05) and increases in HDL-C (+5% vs. -3%; P = 0.05); however, CHO favored reduction in LDL-C (-7% vs. +2.5%; P < 0.05). INS responses to the meal challenge were improved in PRO compared to CHO (P < 0.05) at both 1 hr (-34.3% vs. -1.0%) and 2 hr (-9.2% vs. +46.2%), an effect that remained significant after controlling for weight or fat loss (both P < 0.05). Conclusion A weight loss diet with moderate carbohydrate, moderate protein results in more favorable changes in body composition, dyslipidemia, and post-prandial INS response compared to a high carbohydrate, low protein diet suggesting an additional benefit beyond weight management to include augmented risk reduction for metabolic disease.