Neuroendocrine Consequences of Fasting in Adult Male Macaques: Effects of Recombinant Rhesus Macaque Leptin Infusion

Abstract

Fasting inhibits the gonadotropic axis and stimulates the corticotropic and somatotropic axes. Since leptin is a product of fat cells that has been implicated in the control of both reproduction and metabolism, we hypothesized that the decrease in leptin observed during fasting was responsible for these effects on reproductive and metabolic hormones. Recombinant rhesus leptin (rrhLep) produced in our laboratory was infused (100 µg/h) into fasted adult male rhesus macaques (6–9 kg) beginning at midnight after the first missed meal and continuing until the end of the study. Bioactive luteinizing hormone (LH), testosterone, cortisol and growth hormone (GH) were measured in plasma from samples collected at 15-min intervals for the last 15 h (42–57 h) of the fast. We analyzed pulsatile LH and GH secretion by deconvolution analysis and the orderliness of pulsatile LH and GH release by the approximate entropy (ApEn) statistic. There was no difference in LH pulse frequency between control and fasted groups, but there was a significant decrease in the mean concentration of LH released (7.6 ± 1.4 ng/ml control vs. 2.7 ± 0.65 ng/ml fasted) that was not relieved with rrhLep infusions (2.8 ± 0.83 ng/ml). Model-free Cluster analysis confirmed these inferences and also indicated that the peak height was lower in the fasted (4.6 ± 1.0 ng/ml) and the fasted + rrhLep (2.85 ± 1.0 ng/ml) groups compared to controls (16.3 ± 1.4 ng/ml). Testosterone levels reflected those of LH. Fasting resulted in an increase in GH secretory pulse frequency (5.3 ± 0.95 pulses/15 h control vs. 12.8 ± 1.4 pulses/15 h fasted) and this increase was not affected by rrhLep infusion (12.5 ± 1.4 pulses/15 h). In addition, fasting also increased the ApEn (decreased the orderliness) of pulsatile GH secretion, and this characteristic was not relieved with rrhLep infusions. Cortisol levels in fasted animals were 2- to 3-fold higher than those observed in control studies, and this increase was particularly pronounced at the time when the animals expected their first meal of the day. The increase in circulating cortisol observed in fasted animals was not affected by rrhLep infusion. Glucose levels at the end of the sampling period were 80 mg/dl in controls, 48 mg/dl in fasted animals and 58 mg/dl in the fasted + rrhLep group. Circulating leptin levels averaged 1.2 ± 0.37 ng/ml in control animals, 0.7 ± 0.2 ng/ml in fasted animals and 10.1 ± 5.6 ng/ml in fasted animals infused with rrhLep. These studies suggest that intravenous replacement with homologous leptin does not reverse the acute changes in GH, LH and cortisol secretion observed with fasting in the adult male macaque.

Short‐term fasting leads to inhibition of responsiveness to LH‐stimulated testosterone secretion in the adult male bonnet monkey

“…In this study, the findings that short-term fasting causes suppression of the pituitary-gonadal axis activity in the adult male bonnet monkey are in accordance with similar findings reported previously in other species [Bronson, 1998;Cameron & Nosbisch, 1991;Lado-Abeal et al, 2000; Note that T concentrations were highest at 60 min post-rhLH injection. Arrow indicates injection of rhLH.…”

“…Analysis of 11bHSD1 activities in Leydig cells of subordinate males was lower compared with that of dominant males, indicating that high corticosterone concentration and low 11bHSD1 activity in Leydig cells caused lower T production in subordinate males [Monder et al, 1994]. It should be noted that increased cortisol levels in fasted monkeys as observed in the present study was also reported by other groups Lado-Abeal et al, 2000]. However, experimentally when cortisol levels were elevated by way of exogenous administration of hydrocortisone acetate, inhibition of LH/T secretion in fed monkeys was not observed suggesting lack of cortisol effect on T secretion .…”

Intracerebroventricular infusion of leptin elevates the secretion of luteinising hormone without affecting food intake in long-term food-restricted sheep, but increases growth hormone irrespective of bodyweight

“…In contrast, i.v. infusion of leptin to adult male monkeys did not reverse the fasting-induced alterations in the secretion of luteinising hormone (LH), GH, cortisol or testosterone (Lado-Abeal et al 2000). In this later experiment, however, leptin treatment did not begin until 11 h after the onset of the fast.…”

Effect of Fasting on Cocaine-Amphetamine-Regulated Transcript, Neuropeptide Y, and Leptin Receptor Expression in the Non-Human Primate Hypothalamus

“…Inhibition of the reproductive axis occurs in response to a 2- to 3-day fast in rodents, monkeys and man [3, 8, 12, 35, 52]. Although some exceptions have been reported [53,54,55], leptin administration can reverse fasting-induced inhibition of the hypothalamic-gonadotropic axis [8, 13, 56]. The reproductive axis in particular may be subject to leptin control since leptin replacement reversed fasting induced suppression of pulsatile LH secretion, but failed to normalize either the thyroid stimulating hormone, thyroid hormone or insulin-like growth factor-1 secretion [56] Leptin’s action on the reproductive neuroendocrine axis does not appear to be mediated by melanocortin receptors [21].…”