Body weight decreases induced by estradiol in female rhesus monkeys are dependent upon social status
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.
References (96)
- et al.
Effects of social factors on adrenal weight and related physiology of Macaca fascicularis
Physiol Behav
(1984) - et al.
Quantifying food intake in socially housed monkeys: social status effects on caloric consumption
Physiol Behav
(2008) - et al.
Polymorphisms in the serotonin reuptake transporter gene modify the consequences of social status on metabolic health in female rhesus monkeys
Physiol Behav
(2008) - et al.
- et al.
Psychosocial influences on female 'protection' among cynomolgus macaques
Atherosclerosis
(1984) - et al.
Corticotropin releasing factor, corticosteroids, stress, and sugar: energy balance the brain and behavior
- et al.
The corticotropin-releasing factor family of peptides and CRF receptors: their roles in the regulation of energy balance
Eur J Pharmacol
(2002) - et al.
Gender differences in associations between body mass index and DSM-IV mood and anxiety disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions
Ann Epidemiol
(2008) - et al.
Food intake and the menstrual cycle: a retrospective analysis, with implications for appetite research
Physiol Behav
(1995) - et al.
Exercise-associated amenorrhea: a distinct entity?
Am J Obstet Gynecol
(1981)