Macronutrient Determinants of Obesity, Insulin Resistance and Metabolic Health

Abstract

Obesity caused by the overconsumption of calories has increased to epidemic proportions. Insulin resistance is often associated with an increased adiposity and is a precipitating factor in the development of cardiovascular disease, type 2 diabetes, and altered metabolic health. Of the various factors contributing to metabolic impairments, nutrition is the major modifiable factor that can be targeted to counter the rising prevalence of obesity and metabolic diseases. However, the macronutrient composition of a nutritionally balanced "healthy diet" are unclear, and so far, no tested dietary intervention has been successful in achieving long-term compliance and reductions in body weight and associated beneficial health outcomes. In the current review, we briefly describe the role of the three major macronutrients, carbohydrates, fats, and proteins, and their role in metabolic health, and provide mechanistic insights. We also discuss how an integrated multi-dimensional approach to nutritional science could help in reconciling apparently conflicting findings.

Keywords: insulin resistance; macronutrients; obesity.

Figure 1

Potential molecular mechanisms mediating the adverse consequences of high fructose intake. DHAP: Dihydroxyacetone phosphate. CPT1a: Carnitine palmitoyltransferase 1 (hepatic isoform a). ACADL: Long-chain specific acyl-CoA dehydrogenase.

Figure 2

Potential molecular mechanisms for long-chain fatty acid (LCFA)-induced insulin resistance. DAG: diacylglycerol; TAG: triglyceride; ROS: reactive oxygen species.

Figure 3

Potential molecular mechanisms for protein and branched chain amino acid (BCAA)-induced insulin resistance. GCN2: General control nonderepressible 2 kinase; FGF21: Fibroblast growth factor 21; UCP1: Uncoupling Protein 1; IGF-1: Insulin-like growth factor-1; mTORC1: Mammalian target of rapamycin complex 1; SREBP: Sterol regulatory element-binding protein; S6K1: Ribosomal S6 Kinase 1.

Figure 4

The relationship between protein and carbohydrate intake and median lifespan in mice. The lifespan remains constant along the black isolines on the surfaces, and the numbers on surfaces indicate the magnitude of lifespan (in weeks) along the isolines. The shortest lifespan is shown in blue and the longest lifespan in red. Mice fed diets with the lowest protein–carbohydrate ratio (red line) had the longest lifespan, while those fed high protein–low carbohydrate diets had the shortest lifespan [185,218] (Reprinted with permission from refs. [185,218]. Copyright 2021 Solon-Biet, SM, Simpson SJ).

Figure 5

The relationship between protein and non-protein (fat and carbohydrate intake) and decrease in body weight from baseline on carbohydrate restricted/ketogenic diets [167] (Reprinted with permission from ref [167]. Copyright 2021 Wali, J.A). Two-dimensional geometric framework (GF) surfaces showing the relationship between the intake of energy from protein and non-protein (fat and carbohydrate) sources and the decline in body weight (kg) in study participants. In the GF surfaces, red colour shows the maximum and blue colour shows the minimum decrease in body weight, and black dots represents the intake of protein and non-protein energy reported in each study. Human studies of 2.5–6 months duration which reported the average daily intake of macronutrients of the study participants on carbohydrate-restricted diets and their mean decrease in body weight (n = 14 studies) achieved on these diets (vs. baseline measurements) were included in these GF plots. The decrease in body weight became greater as the protein intake increased (red areas of the surface). Adapted with permission of the authors Wali et al. 2020 [167].