Obesity and malnutrition similarly alter the renin–angiotensin system and inflammation in mice and human adipose

doi:10.1016/j.jnutbio.2017.06.008

The Journal of Nutritional Biochemistry

Volume 48, October 2017, Pages 74-82

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Abstract

The main goal of the present study was to evaluate the metabolic profile, inflammatory markers and the gene expression of the renin–angiotensin system (RAS) components in the visceral adipose tissue of eutrophic, obese and malnourished individuals and mice models of obesity and food restriction. Male Swiss mice were divided into eight groups and fed different levels of food restriction (20%, 40%, or 60%) using standard or high-fat diet. Metabolic profile and adipose tissues were assessed. The expression of AGT (Angiotensinogen), ACE (Angiotensin-converting enzyme), ACE2 (Angiotensin-converting enzyme 2), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in the mice epididymal adipose tissue and the human visceral adipose tissue was assessed. The main findings showed reduced body weight, improved metabolism, decreased adipose tissues weight and reduced adipocyte area in mice submitted to food restriction. Diminished expression of IL-6, TNF-α, AGT, AT1 and ACE was detected in the 20% and 40% food restriction animal groups, although they were increased in the 60% malnourished group. Increased expression of IL-6, TNF-α, AGT and ACE in obese and malnourished individuals was observed. Adipocytes size was increased in obese individuals and reduced in malnutrition. In conclusion, we found that food restriction of 20% and 40% improved the metabolic profile, ameliorated the inflammatory status and down-regulated the RAS in mice. Severe 60% food restriction (malnutrition), however, stimulated a proinflammatory state and increased AGT and ACE expression in the adipose tissue of mice. A similar profile was observed in the adipose tissue of obese and malnourished humans, supporting the critical role of inflammation and RAS as mediators of metabolic disorders.

Graphical abstract

Introduction

The increasing prevalence of obesity [1], [2] is a matter of great concern worldwide. Obesity is considered a risk factor for cardiovascular diseases, and it is one of the key features of the metabolic syndrome (MetS) [3]. The main comorbidities of MetS include hypertension, dyslipidemia, stroke, type 2 diabetes mellitus and some types of cancer [4]. Obesity is characterized by the accumulation of body fat resulting from an imbalance between food intake and energy expenditure [3], [5]. Recently, obesity has been described as a proinflammatory state associated with elevation of tissue and circulating levels of proinflammatory enzymes, procoagulant factors, cytokines and chemokines, demonstrating that the adipose tissue modulates not only its biology but also the reproductive and endocrine systems, immunity, inflammation and insulin sensitivity [6]. There are evidence suggesting that the white adipose tissue (WAT) becomes hypertrophied due to macrophage infiltration that secretes proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and some interleukins, such as interleukin-6 (IL-6) [7].

A growing number of studies describe the importance of the renin–angiotensin system (RAS) in regulating the metabolism and the development of cardiovascular and inflammatory diseases [8], [9], [10]. Various components of the RAS have been identified in the adipose tissue [11]. Recent studies have shown that RAS significantly modulates the metabolism and endocrine function of adipocytes [12]. Further RAS components may be modulated according to different obesity degrees [13].

Caloric restriction, on the other hand, is characterized by a low-caloric diet regimen without causing malnutrition. Experimental studies in rodents and rhesus monkeys showed that partial caloric restriction increases longevity and prevents or delays the occurrence of chronic diseases such as diabetes, atherosclerosis, cardiomyopathy, tumors, autoimmune diseases, and renal and respiratory problems [14], [15], [16], [17], [18], [19]. Some evidence have shown that the maximum positive effect occurs with restrictions of 55% to 60% compared to baseline intake [20], [21]. Clinical studies further showed that weight loss diminishes the inflammatory status in obesity and subsequent comorbidities by decreasing the number of circulating inflammatory molecules [22]. However, a significant loss in body weight can induce a state of malnutrition. Malnourished individuals may present inflammatory, hypermetabolic and hypercatabolic conditions, in addition to reduced albumin levels [23], [24], [25], [26].

We, therefore, hypothesize that different levels of food restriction, associated or not with a high-fat diet, may differently modulate adipose tissue inflammatory state and RAS regulation, preventing metabolic alterations as observed in obesity. Thus, the purpose of the present study was to evaluate the metabolic profile and expression of inflammatory markers and RAS components in adipose tissue of mice submitted to different food restriction degrees and to validate such profile in the visceral adipose tissue of eutrophic, obese and malnourished humans.

Section snippets

Animal study

The experiment was conducted with 64 Swiss mice (male, 4 weeks old) divided into 8 groups (n=8 each) and fed with the following respective experimental diets for 8 weeks. The groups were divided into the following: standard diet (ST) ad libitum, ST-20% food restriction, ST-40% food restriction, ST-60% food restriction, high-fat diet (HFD) ad libitum, HFD-20% food restriction, HFD-40% food restriction and HFD-60% food restriction. All procedures performed in studies involving animals were in

Results

Food intake (Fig. 1A); energy intake (Fig. 1B); the body weight (Fig. 1C and D); epididymal (Fig. 1E), retroperitoneal (Fig. 1F) and mesenteric (Fig. 1G) WAT weights; and adipocyte area (Fig. 1H and I) were reduced in mice fed a standard diet and submitted to food restriction. For mice fed a high-fat diet, food intake; body weight; epididymal, retroperitoneal and mesenteric adipose tissues weight; and adipocyte surface area were also decreased in all groups under restriction as compared to

Discussion

This study describes for the first time that although mild to moderate (20%–40%) restriction can improve the metabolic and inflammatory status, a more severe restriction (60%) does not present the same protective effect in mice. Also, decreased inflammatory status in mild to moderate restriction in mice was associated with down-regulation of key RAS components, such as AGT and ACE in the adipose tissue. Interestingly, we found a similar profile in obese and malnourished humans, also presenting

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Citation Excerpt :
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^☆: Conflict of interests: The authors have nothing to disclose.

^☆☆: Funding: This work was supported by grants from the Coordenadoria de Aperfeiçoamento do Pessoal de Nível Superior, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Fundação de Amparo à Pesquisa de Minas Gerais, and Faculdades Integradas Pitágoras, Montes Claros, Montes Claros, Minas Gerais, Brazil.

¹: Equally contributed to this study.

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Research ArticleObesity and malnutrition similarly alter the renin–angiotensin system and inflammation in mice and human adipose☆,☆☆

Abstract

Graphical abstract

Introduction

Section snippets

Animal study

Results

Discussion

J Nutr

Lancet

Regul Pept

Int J Biochem Cell Biol

Exp Gerontol

Int J Biochem Cell Biol

J Nutr

Crit Rev Oncol Hematol

Mol Aspects Med

J Acad Nutr Diet

Methods

Thromb Res

Arch Med Res

The perfect storm: obesity, adipocyte dysfunction, and metabolic consequences

Clin Chem

Muscular strength is inversely related to prevalence and incidence of obesity in adult men

Obesity

Adipokines in inflammation and metabolic disease

Nat Rev Immunol

Inflammation and metabolic disorders

Nature

Inflammation-sensitive plasma proteins are associated with future weight gain

Diabetes

Improved lipid and glucose metabolism in transgenic rats with increased circulating angiotensin-(1–7)

Arterioscler Thromb Vasc Biol

Mas deficiency in FVB/N mice produces marked changes in lipid and glycemic metabolism

Diabetes

Angiotensinogen-deficient mice exhibit impairment of diet-induced weight gain with alteration in adipose tissue development and increased locomotor activity

Endocrinology

Research Article
Obesity and malnutrition similarly alter the renin–angiotensin system and inflammation in mice and human adipose☆,☆☆