Functional variability in corticosteroid receptors is a major component of strain differences in fat deposition and metabolic consequences of enriched diets in rat
Introduction
Prevalence of obesity is growing in industrialized countries, with many health and social consequences [1]. In both humans and rats, obesity appears to be inherited as a polygenic trait [2]. Interindividual differences in vulnerability to weight gain and fat deposition are exacerbated by environmental pressure, such as overconsumption of dietary fat and stressful lifestyle. Human abdominal obesity has been associated with perturbations in the hypothalamo-pituitary-adrenal (HPA) axis [3]. These alterations, among others, concern glucocorticoid production and metabolism [4]. Moreover, most obesity syndromes in animals depend on functional HPA axis [5]. Our aim is to explore the nutritional consequences of genetic variations in HPA axis activity. Glucocorticoid actions on target tissues, such as liver or fat, are dependent not only on circulating levels but also on hormone bioavailability (plasma transcortin and 11β-hydroxysteroid dehydrogenase [6], [7]) and on the transduction efficiency at the level of their receptors [8]. Indeed both corticosteroid receptors, that is, mineralocorticoid (MR) and glucocorticoid (GR) receptors, are involved in metabolic regulations and in the development of fat stores and their pathologic consequences (such as the metabolic syndrome [9], [10], [11]). After adrenalectomy (ADX) in rat, the weight gain is increased to normal by MR activation with low doses of corticosterone or MR agonists via an up-regulation of food intake and efficiency [12] and adipogenesis [13], [14]. It is decreased by GR activation with high doses of corticosterone or GR agonists via catabolic effects on fat and protein stores [15]. The proteolysis induced by GR activation is more marked than the lipolysis, altering the body distribution of lipid stores to increase abdominal fat mass at the expense of muscular mass [15]. Cushing syndrome in humans and animals illustrates the link between high glucocorticoids and accumulation of central fat [16]. Glucocorticoids stimulate also preadipocyte differentiation and drive adipose tissue distribution and function via both MR and GR [13], [17]. The accumulation of abdominal fat they favor in rodents and humans is involved in the metabolic disturbances linked to obesity [18]. Indeed, in contrast to the subcutaneous fat, the abdominal fat mass exhibits high rates of basal and hormone-induced lipolysis (including at metabolically inappropriate times [19]). Glucocorticoids also induce hepatic gluconeogenesis and exert anti-insulin actions that worsen type 2 diabetes mellitus [4].
The present experiments aimed to explore the involvement of functional differences in MR and GR in nutritional differences between 2 inbred rat strains, Fischer 344 (F344) and LOU/C (LOU), especially in their vulnerability or resistance to fat deposition, respectively, and their sensitivity to enriched diets (gene × environment interaction). F344 rats have been shown to store excess triglycerides in liver and muscle and to exhibit abdominal fat accumulation, insulin resistance, and dyslipidemia under standard diet [20]. LOU rats are characterized by healthy aging and lower fat mass compared with other rat strains [21]. We have shown that, in contrast with F344 rats that develop visceral obesity in response to high-fat diet, LOU rats are resistant to diet-induced obesity [22]. Moreover, we have shown that LOU rats exhibit lower corticosterone levels across the circadian rhythm and during the recovery following a restraint stress as compared with F344 rats [23]. The first part of our study was devoted to compare the efficiency of both corticosteroid receptor types between F344 and LOU strains. To that end, we measured the decrease of urinary Na+/K+ ratio induced via MR activation by aldosterone [24] and the decrease of circulating lymphocyte counts exerted via GR activation by dexamethasone (DEX) in these strains [25]. To explore the metabolic consequences of the functional differences that we found in their corticosteroid receptors, physiologic (food intake, body weight gain) and biochemical (plasma corticosterone, insulin, leptin, glucose, and free fatty acids) measurements were made under standard diet, then under free choice between chow and pork lard, and lastly under an imposed high-fat/high-sugar diet in F344 and LOU rats submitted to ADX and to substitution treatments with MR or GR agonists. Because the nutritional differences between F344 and LOU rats could also involve catabolic processes, the third part of our study was devoted to the measurements by indirect calorimetry of energy expenditure and substrate oxidization in control, fasting, and refeeding conditions. We also measured the effects of a norepinephrine acute treatment and of ADX ± MR/GR agonists under standard and high-fat diets on calorimetric data in both strains. This study demonstrates large differences in MR- and GR-related actions between F344 and LOU rats (Fig. 1, at the disposal of the reader from the start) and their role in vulnerability to fat deposition, metabolic disorders linked to visceral obesity, and energy expenditure.
Section snippets
Animals and diets
Experiments were conducted in accordance with the principles and guidelines of the French legislation on animal welfare, Journal Officiel no. 87-848, and under veterinary supervision. All rats were born and raised in the laboratory from LOU (Harlan, Lyon, France) and F344 breeders (Iffa Credo, L'Abresle, France). They were housed in standard collective cages in a temperature-controlled room (23°C ± 1°C) with a 12:12-hour light-dark cycle (lights on at 7:00 am). In standard conditions, they were
Effect of aldosterone on excretion of electrolytes
F344 and LOU rats showed the same urinary Na+/K+ ratio in control condition (Fig. 2A), but aldosterone decreased this ratio in LOU rats only (P < .01).
Effect of DEX on circulating lymphocytes
In control condition, lymphocyte count was higher in LOU than in F344 rats (P < .001) (Fig. 2B). DEX reduced lymphocyte count in both strains, but to a greater extent in LOU than in F344 rats (−80.30% ± 0.30% vs −73.3% ± 0.30%, P < .05).
Food intake
In sham condition, caloric intake did not differ between the F344 and LOU strains. In other conditions (ADX, or
Discussion
We showed previously that the modulation by corticosterone of food intake, body composition, and biochemical parameters related to energy metabolism differs between F344 and LOU strains [32]. The aim of the present study was to distinguish MR from GR actions in these nutritional differences. The first part was devoted to compare MR and GR efficiency between F344 and LOU strains. To that end, we measured the decrease of urinary Na+/K+ ratio induced via MR activation by aldosterone and the
Conclusion
This study confirms the involvement of genetic factors in individual vulnerability to the unfavorable impact of stressful environment, that is, of high glucocorticoid levels, on the consequences of inadequate food choices and overfeeding [42], [52], [59]. The F344 rat strain constitutes a relevant model of the involvement of GR activation in food preference for high-calorie diets, abdominal fat deposition, type 2 diabetes mellitus, and other deleterious consequences of visceral obesity [18],
Acknowledgment
This work was partly supported by the Institut de Recherche en Nutrition Humaine d'Aquitaine and the INSERM ATC Nutrition.
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