Sex Differences in Androgen Regulation of Metabolism in Nonhuman Primates

Abstract

The in-depth characterization of sex differences relevant to human physiology requires the judicious use of a variety of animal models and human clinical data. Nonhuman primates (NHPs) represent an important experimental system that bridges rodent studies and clinical investigations. NHP studies have been especially useful in understanding the role of sex hormones in development and metabolism and also allow the elucidation of the effects of pertinent dietary influences on physiology pertinent to disease states such as obesity and diabetes. This chapter summarizes the current state of our understanding of androgen effects on male and female NHP metabolism relevant to hypogonadism in human males and polycystic ovary syndrome in human females. This review will also focus on the interaction between altered androgen levels and dietary restriction and excess, in particular the Western-style diet that underlies significant human pathophysiology.

Figure 1. Testosterone deficiency induces a multilocular phenotype in male WAT

Insulin-stimulated WAT explants from castrated (CAS, A, upper panels, and B, both panels) and testosterone-replaced (TEST, A, lower panels) adult male macaques were labeled with green fluorescent fatty acid BODIPY-C12 (lipid droplets) and red fluorescent wheat germ agglutinin (blood vessels) and analyzed by confocal microscopy. Arrowheads indicate small multilocular adipocytes in CAS (upper panels) and small unilocular adipocytes in TEST (lower panels) WAT. Scale bar, 50 μm. Adapted from [47].

Figure 2. The suppression of lipolysis by androgens in female WAT

Female rhesus macaques were randomly assigned at 2.5 years of age (near menarche) to receive either cholesterol (C; n = 20) or testosterone (T; n = 20)-containing silastic implants to elevate T levels 5-fold above baseline. Half of each of these groups was then fed either a low-fat monkey chow diet or a WSD, resulting in four treatment groups (C, control diet; T alone; WSD alone; T + WSD; n = 10/group) that were maintained until the current analyses were performed at 5.5 years of age (3 years of treatment, young adults). OM (panel A) and SC-WAT (panel B) biopsies were collected and analyzed longitudinally for changes in basal (Bas) and isoproterenol (Iso)-stimulated lipolysis. In year 3 of treatment, basal lipolysis was blunted in the T and T + WSD groups in both WAT depots, while isoproterenol-stimulated lipolysis was significantly blunted in the T and T + WSD groups only in SC-WAT. Adapted from [49].

Figure 3. The effect of hyperandrogenemia on female adipocytes

A, Insulin-stimulated free fatty acid (FFA) uptake in adipocytes is coupled to unidirectional FFA esterification, followed by the packaging of triglyceride into the central lipid droplet (LD). Micro LDs are strategically located at the interface of the cytoplasm, endoplasmic reticulum, and the central LD, being responsible for and/or associated with insulin-stimulated triglyceride synthesis and packaging in unilocular adipocytes [80]. The opposite process of triglyceride degradation, termed lipolysis, is potentiated by β-adrenergic stimuli provided by local sympathetic innervation. B, hyperandrogenemia (T excess) inhibits basal lipolysis both in subcutaneous (SC) and visceral omental (OM) WAT depots, while significantly suppressing β-agonist-stimulated lipolysis in SC-WAT. In animals fed a control low-fat chow diet, the T-induced lipolytic defect does not evoke adipocyte hypertrophy and insulin resistance. C, T-induced suppression of lipolysis persists in animals fed a WSD with the same depot specificity. Additionally, insulin-stimulated FFA uptake in OM adipocytes is significantly elevated in response to a combined exposure to hyperandrogenemia and WSD. In combination, elevated FFA uptake and suppressed lipolysis are associated with OM adipocyte hypertrophy, abdominal obesity, and systemic insulin resistance.

Figure 4. The effect of T deficiency on male adipocytes and skeletal muscle

A, The cytoarchitecture of a unilocular adipocyte (described in Figure 3A). B, in control diet-fed animals, T deficiency induces a multilocular phenotype, the appearance of a population of smaller adipocytes, impairs insulin signaling in WAT, and triggers rapid muscle loss (sarcopenia). C, WSD stimulates visceral (OM) and SC-WAT hypertrophy, resulting in sarcopenic obesity and insulin resistance. D, the reversal of WSD with caloric restriction causes partial normalization of adipocyte size and reduces fat mass, but does not eliminate systemic insulin resistance and the progression of sarcopenia.