Obesity: considerations about etiology, metabolism, and the use of experimental models

Abstract

Studies have been conducted in order to identify the main factors that contribute to the development of obesity. The role of genetics has also been extensively studied. However, the substantial augmentation of obesity prevalence in the last 20 years cannot be justified only by genetic alterations that, theoretically, would have occurred in such a short time. Thus, the difference in obesity prevalence in various population groups is also related to environmental factors, especially diet and the reduction of physical activity. These aspects, interacting or not with genetic factors, could explain the excess of body fat in large proportions worldwide. This article will focus on positive energy balance, high-fat diet, alteration in appetite control hormones, insulin resistance, amino acids metabolism, and the limitation of the experimental models to address this complex issue.

Keywords: diet; experimental models; fat; ghrelin; leptin; obesity.

Figures

Figure 1

Evidence suggests that the mechanisms inhibiting both appetite and caloric ingestion may be impaired in obese individuals. Note: This is not yet consensual in the literature, although many authors have been trying to clarify how the mechanisms regulating hunger and satiety behave in this population. Reproduced with the permission of The American Physiological Society from Little TJ, Horowitz M, Feinle-Bisset C. Modulation by high-fat diets of gastrointestinal function and hormones associated with the regulation of energy intake: implications for the pathophysiology of obesity. Am J Clin Nutr. 2007;86(3):531–541. Abbreviations: CCK, cholecystokinin; GLP-1, glucagon-like peptide 1; OXM, oxyntomodulin; PP, pancreatic polypeptide; PYY, peptide YY.

Figure 2

Postulated mechanisms for fatty acid control of gene transcription. The FA per se, FA-CoA, or FA metabolite modulate (±) transcription of a responsive gene, encoding a protein involved in FA transport or metabolism, through various non-mutually selective potential mechanisms. Step 1: a signal transduction cascade is initiated to induce a covalent modification of a TF, thereby modifying its transcriptional potency. Step 2: the FA itself or its derivative acts as a ligand for a TF, which then can bind DNA at a FA response element and activate or repress transcription. Steps 3, 4 and 5: FA can act indirectly via alteration in either TF mRNA stability (Step 3) or gene transcription (Step 4), resulting in variations of de novo TF synthesis (Step 5) with an impact on the transcription rate of genes encoding proteins involved in FA transport or metabolism. On binding to the eognate response element, TF acts either as a monomer (Step 6), a homodimer, or a heterodimer with TF+, a different TF (Step 7). Notes: Reproduced with the permission of the American Society for Biochemistry and Molecular Biology from Duplus E, Glorian M, Forest C. Fatty acid regulation of gene transcription. J Biol Chem. 2000;275(40):30749–30752. Copyright © 2000, by the American Society for Biochemistry and Molecular Biology. Abbreviations: FA, fatty acids; FA-CoA, fatty acyl-CoA; TF, transcription factor.

Figure 3

Adaptation of muscle metabolism to a high availability of lipids. Note: Reduced participation of carbohydrates and high amino acid participation in anaplerotic reactions are observed, activating the hexosamine pathway. Abbreviations: AA, amino acid; CHO, carbohydrate; CoA, coenzyme A; NH3, ammonia.

Figure 4

Micrograph of mitochondrial impairment caused by aspartate and asparagine supplementation in a rat model. Notes: The left panel shows the soleus muscle of the sedentary control group (15,000×) and the right panel shows the soleus muscle of the supplemented group (aspartate and asparagine) (7000×).