Body weight decreases induced by estradiol in female rhesus monkeys are dependent upon social status

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Abstract

Gonadal steroids regulate appetite and thus body weight. In addition, continuous exposure to stressors negatively influences appetite through circuits likely distinct from those of gonadal steroids. The occurrence of adverse metabolic consequences due to chronic exposure to psychosocial stressors is twice as frequent in women as men, implicating a role for ovarian hormones, estradiol (E2) and progesterone (P4), in modulating stress-induced changes in appetite. Using social subordination in female macaques as a model of social stress, the current study tested the hypothesis that subordinate females would lose more weight during E2 treatment and gain less weight during P4 administration than dominant females. Because polymorphisms in the gene encoding the serotonin transporter (5HTT; SCL6A4) are known to alter responsivity to stress, we hypothesized that weight loss during E2 administration would be greatest in females with the short variant (s-variant) allele of 5HTT. Dominant females were significantly heavier than subordinate animals throughout the study, a result consistent with previous accounts of food intake when animals are fed a low-fat, high-fiber diet. Females with the s-variant 5HTT genotype weighed significantly less than l/l animals. Dominant animals lost significantly more weight than subordinate animals during E2 treatment. Administration of P4 blocked the weight-reducing effects of E2 in all females, regardless of social status. These data provide evidence that social subordination modulates the influence of ovarian steroid hormones on body weight in female rhesus monkeys independent of 5HTT genotype. Given the prosocial effects of these steroids, future studies are necessary to determine whether status differences in E2-induced weight loss are due to diminished food intake and or increases in energy expenditure and how the change in energy availability during E2 treatments relates to a female's motivation to interact with conspecifics.

Research Highlights

► Social status and serotonin transporter polymorphism affect overall body weight ► Estradiol-induced weight loss is greater in dominant than subordinate animals ► Progesterone in concert with estradiol increased body weight in all females

Introduction

Rhesus macaque females, when housed socially, organize themselves into a linear dominance hierarchy that is enforced by the constant harassment and threat of aggression towards subordinate members by more dominant animals [1], [2]. Subordinate females show reductions in body weight and metabolic hormones [3], [4], including reduced fat mass and circulating leptin concentrations in comparison to dominant animals [5] when fed a standard low-calorie monkey chow [6]. These metabolic alterations are accompanied by disruptions in limbic–hypothalamic–pituitary–adrenal axis (LHPA) activity, as subordinate females are hypercortisolemic due to diminished glucocorticoid negative feedback [4], [7], [8]. Heightened activity of corticotropin-releasing hormone (CRH) in rodents mediates the anorectic effects of exposure to chronic stressors [9], [10], [11] and could be the underlying cause of reductions in body weight seen in subordinate animals.

The occurrence of adverse metabolic consequences due to chronic psychosocial stressors is more prevalent in women than in men, as women are twice as susceptible than men to developing eating disorders and altered metabolism [12], [13], [14]. This increased vulnerability in women implicates the role of the ovarian steroid hormones, estradiol (E2) and progesterone (P4), in affecting body weight and metabolism. Indeed, E2 replacement and high estrogen levels associated with stages of the ovarian cycle are linked to decreases in body weight [15] and food intake [16], [17], [18], [19] in rodents and humans. Periods of elevated P4 coincide with increases in food intake and body weight in women [15], [19], [20], [21] and synthetic progestins are known to increase body weight [22]. While the effects of E2 and P4 on body weight are well described, it is unclear how the effects of social stress interact with those of gonadal steroids to regulate body weight.

Individual vulnerability to adverse health outcomes associated with chronic exposure to stressors is likely affected by a number of genetic factors. In particular, polymorphisms in the gene (SCL6A4) that encodes the serotonin transporter (5HTT) [23] are associated with greater vulnerability to environmental stressors in monkeys and in people. The short promoter length variant (s-variant) of 5HTT has reduced transcriptional activity in humans [24] and individuals with this short promoter allele have a higher incidence of psychopathology [23] than individuals homozygous for the long 5HTT allele (l/l). Rhesus monkeys also show homologous polymorphisms in 5HTT [25], [26] and the s-variant allele increases individual susceptibility to adverse effects of social subordination on reproduction and metabolism [5], [27].

The present study was designed to determine how social stress, resulting from social subordination, interacts with gonadal steroids to influence body weight in females. Using adult ovariectomized rhesus monkeys, we hypothesized that replacement therapy with E2 would produce the greatest decrements in body weight in subordinate compared with more dominant animals and that this effect would be exacerbated by the short promoter length allele in the 5HTT gene. Because progestins promote weight gain, the study determined whether administration of P4 would attenuate the effects of E2.

Section snippets

Animals

Subjects included 39 ovariectomized adult female rhesus monkeys (13–17 years old) socially housed in indoor-outdoor runs in small social groups without males (n = 4 or 5 per group) as previously described [5]. Animals were fed standard monkey chow (low-fat, high-fiber diet from PMI Lab Diets, #5038, St. Louis MO) ad libitum twice-daily via two chow bins from which multiple animals could access food simultaneously. We observe no evidence of more dominant monkeys restricting subordinate females from

Social status categorization

Fig. 1 shows rates of aggression received and submissive behavior emitted by monkeys at each social dominance rank position, independent of 5HTT genotype. These data were derived from two 30-min group scans of aggressive and submissive behaviors obtained each week of the four treatment conditions. Hormone treatments did not alter the dominance hierarchy in any of the groups. As expected, subordinate females (ranks 3–5) received significantly more aggression from higher ranking cage mates (F 1, 8

Discussion

Subordinate females, receiving more aggression and emitting more submissive behavior, maintained lower body weights, abdominal adiposity, and peripheral leptin than dominant females. Furthermore, as observed previously [5], dominant females with an l/l 5HT genotype were heavier than dominant s-variant females throughout the study period. These status differences is body weight are consistent with previous reports of status-dependent body weight differences [5], [40] due to diminished food

Acknowledgements

The study was conducted with the invaluable expert technical assistance of Jennifer Whitley, Holly Jarrell, Dr. Jacquelyn Hoffman, Marta Checchi and Jeff Fisher. The study was supported by NIH grants HD46501 and RR00165, and F31MH085445 (V.M.). The YNPRC is fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care, International.

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