High-Protein Intake during Weight Loss Therapy Eliminates the Weight-Loss-Induced Improvement in Insulin Action in Obese Postmenopausal Women

Abstract

High-protein (HP) intake during weight loss (WL) therapy is often recommended because it reduces the loss of lean tissue mass. However, HP intake could have adverse effects on metabolic function, because protein ingestion reduces postprandial insulin sensitivity. In this study, we compared the effects of ∼10% WL with a hypocaloric diet containing 0.8 g protein/kg/day and a hypocaloric diet containing 1.2 g protein/kg/day on muscle insulin action in postmenopausal women with obesity. We found that HP intake reduced the WL-induced decline in lean tissue mass by ∼45%. However, HP intake also prevented the WL-induced improvements in muscle insulin signaling and insulin-stimulated glucose uptake, as well as the WL-induced adaptations in oxidative stress and cell structural biology pathways. Our data demonstrate that the protein content of a WL diet can have profound effects on metabolic function and underscore the importance of considering dietary macronutrient composition during WL therapy for people with obesity.

Keywords: amino acids; calorie restriction; high protein diet; insulin resistance; insulin sensitivity; protein; skeletal muscle; weight loss.

Conflict of interest statement

SK is a shareholder of Aspire Bariatrics and has served on Scientific Advisory Boards for Takeda Pharmaceuticals and NovoNordisk. GIS, JY, SCK, DNR, AO, BWP, and BM declare no conflict of interest.

Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. Changes in body weight and composition and insulin-stimulated glucose uptake

Percent changes in body mass (A), intra-hepatic triglyceride (IHTG) content (B), and intra-abdominal adipose tissue (IAAT) volume (C), percent contribution of fat-free mass (FFM) to total weight loss (D), and absolute (μmol/kg FFM per min) and relative (percent) changes in insulin-stimulated glucose rate of disappearance (Rd) (E and F) before and after the diet intervention in the weight-maintenance (WM) group (n = 7) and in subjects who consumed either the standard weight loss (WL; n = 10) or weight loss high-protein (WL-HP; n = 10) diets. Data are expressed as mean ± SEM. * Value significantly different from corresponding value in the WM group (P † Value significantly different from corresponding value in the WL group (P <0.05). ‡ Value significantly different from value in the WM and WL-HP groups (P <0.05).

Figure 2. Intramyocellular signaling elements before and after weight loss

Weight loss-induced changes in p-AKTSer473 (A), p-AMPKThr172 (B), p-mTORSer2448 (C), and p-4E-BP1Thr37/46 (D) in muscle during basal, postabsorptive conditions (white bars) and the hyperinsulinemic-euglycemic clamp (black bars) in subjects consuming the standard weight loss (WL) and weight loss high protein (WL-HP) diets. Data (n = 6–8) are expressed as mean ± SEM. * Value significantly different from corresponding basal value (P < 0.05). † Value significantly different from all other values (P <0.05). # Significant main effect of clamp (P <0.05). See also Figure S2.

Figure 3. Expression of genes involved in lipogenesis, and fatty acid oxidation and mitochondrial function in muscle

Expression of genes involved in lipogenesis [A: carbohydrate response element binding protein (CHREBP), B: elongation of very long-chain fatty acids protein 6 (ELOVL6), C: fatty acid desaturase 1 (FADS1), D: fatty acid synthase (FASN), E: stearyl Co-A desaturase (SCD), and F: sterol regulatory element binding transcription factor 1 (SREBF1)], and fatty acid oxidation and mitochondrial function [G: acyl-Coenzyme A dehydrogenase (ACADM), H: cytochrome C oxidase subunit IV (COX4/1), I: carnitine palmitoyl transferase 1 (CPT1B), J: pyruvate dehydrogenase kinase 4 (PDK4), K: peroxisome proliferator activated receptor gamma coactivator 1 alpha (PPARGC1A), and L: uncoupling protein 2 (UCP2)] in muscle before (white bars) and after (black bars) weight loss in subjects consuming the standard weight loss (WL) and weight loss high-protein (WL-HP) diets. Data (n = 6–9) are expressed relative to the housekeeping gene and presented as mean ± SEM, except for ACADM, FASN1 and SCD, which are expressed as median (quartiles). # Significant main effect of weight loss (P <0.05). ‡ Significant main effect of group (P <0.05). See also Table S3.

Figure 4. Expression of genes involved in inflammatory and oxidative stress defense pathways in muscle

Expression of genes involved in inflammatory [A: cluster of differentiation 68 (CD68), C: interleukin-6 (IL6), E: monocyte chemoattractant protein 1 (MCP1), and G: tumor necrosis factor (TNF)]) and oxidative stress defense [B: catalase (CAT), D: glutathione S-transferase alpha 4 (GSTA4), F: peroxiredoxin 3 (PRDX3), and H: superoxide dismutase 1 (SOD1)] pathways before (white bars) and after (black bars) weight loss in subjects consuming the standard weight loss (WL) and weight loss high-protein (WL-HP) diets. Data (n = 6–9) are expressed relative to the housekeeping gene and presented as mean ± SEM, except for IL6, MCP1 and TNF, which are expressed as median (quartiles). * Value significantly different from corresponding basal value (P <0.05). † Value significantly different from all other values (P <0.05). # Significant main effect of weight loss (P <0.05). See also Table S3 and Figure S3.