RFRP3 increases food intake in a sex‐dependent manner in the seasonal hamster Phodopus sungorus

Abstract

| INTRODUC TI ONSoon after the discovery by Tsutsui et al 1 of a hypothalamic neuropeptide with a potent inhibitory effect on the secretion of pituitary luteinising hormone (LH) in quails, an orthologue peptide with a similar inhibitory effect on LH secretion was characterised in rodents by Kriegsfeld et al. 2 Further studies confirmed the reproductive effect of this hypothalamic peptide, now called (Arg) (Phe) related peptide-3 (RFRP3). 3,4 Remarkably, the effect of RFRP3 on LH secretion appears to be sex-dependent because it has been reported to be inhibitory in female rodents, 5,6 although either stimulatory or inhibitory in males. 2,[7][8][9][10][11][12] Increasing evidence now indicates that RFRP3 also affects food intake, exhibiting an orexigenic effect in rats, 7,13 jerboas, 14 mice, ewes and non-human primates. 13 In addition, RFRP3 projections and receptors (GPR147) have been described in the arcuate nucleus, 2,15 a hypothalamic region involved in the control of feeding behaviour, mostly AbstractIn addition to its regulatory role in luteinising hormone secretion, Rfamide-related peptide 3 (RFRP3) has also been reported to modulate food intake in several mammalian species. Djungarian hamsters (Phodopus sungorus), similar to other seasonal mammals, display a remarkable inhibition of RFRP3 expression in winter short-day conditions, associated with decreased food intake and bodyweight. This species is therefore a valuable model for assessing whether RFRP3 might be involved in the seasonal control of feeding behaviour and investigating its possible brain targets. We found that, although both male and female animals exhibit the same robust reduction in Rfrp expression in short-(SD) compared to long-day (LD) conditions, acute central administration of RFRP3 displays sex-dependent effects on food intake. RFRP3 increased food intake in female hamsters in SD or in LD dioestrus, but not in LD prooestrus, indicating that the orexigenic effect of RFRP3 is observed in conditions of low circulating oestradiol levels. In male hamsters, food intake was not changed by acute injections of RFRP3, regardless of whether animals were in SD or LD conditions. Analysing the gene expression of various metabolic neuropeptides in the brain of RFRP3-injected Djungarian hamsters revealed that Npy expression was increased in female but not in male animals. The present study suggests that, in Djungarian hamsters, RFRP3 exhibits a sex-dependent orexigenic effect possibly by inducing increased Npy expression. K E Y W O R D SDjungarian hamster, food intake, neuropeptide Y, RFRP3, sex differences

Role of central kisspeptin and RFRP‐3 in energy metabolism in the male Wistar rat

“…40 We found that with the above physiological data, central administration of α-MSH has been shown to simultaneously decrease food intake and increase lipid oxidation. 43 In addition, reduction of brain-melanocortin signalling consistently results in an increased RER [44][45][46][47] that reported previously in other mammalian species, 7,[9][10][11] as well as in ad lib. fed Wistar rats.…”

“…The two main populations of neurones within the ARC that are responsible for the control of energy metabolism and glucose homeostasis are the orexigenic neuropeptide Y (NPY)/agouti‐related peptide (AGRP)‐expressing neurones and the anorexigenic pro‐opiomelanocortin (POMC)/cocaine‐ and amphetamine‐regulated transcript (CART)‐expressing neurones 20 . In our previous studies in the seasonal Djungarian hamster we showed that central administration of Kp increased body weight as well as NPY‐ and POMC expression, whereas RFRP‐3 increased food intake, body weight and circulating levels of leptin and insulin, without changing NPY‐ and POMC expression in the ARC 7,11 . In the present study, we tested the hypothesis that Kp and RFRP‐3 would also affect energy metabolism in male Wistar rats.…”

“…20 In our previous studies in the seasonal Djungarian hamster we showed that central administration of Kp increased body weight as well as NPY-and POMC expression, whereas RFRP-3 increased food intake, body weight and circulating levels of leptin and insulin, without changing NPY-and POMC expression in the ARC. 7,11 In the present study, we tested the hypothesis that Kp and RFRP-3 would also affect energy metabolism in male Wistar rats. Therefore, we assessed the central effects of Kp and RFRP-3 on feeding behaviour, energy metabolism and glucose homeostasis in this species and revealed possible hypothalamic pathways involved in the reported metabolic effects.…”

“…Thus, it is not that surprising that, recently, Kp and RFRP-3 have also been linked to the control of food intake, body weight regulation and glucose homeostasis. [5][6][7] The scarce and scattered data so far point towards RFRP-3 having an orexigenic effect in different mammalian species [7][8][9][10][11] and Kp having an anorexigenic effect. 10,12 Regarding glucose homeostasis, it has been shown that female mice with a knockout (KO) for the Kp receptor Kiss1r are glucose intolerant, 5 whereas i.p.…”

Daily and Estral Regulation of RFRP-3 Neurons in the Female Mice

“…Given the inhibitory effect of RFRP-3 on LH secretion [24,35,52], our findings support that RFRP-3 neurons facilitate the gating of the LH surge at the right time of the day and stage of the estrous cycle. However, given that RFRP-3 is now reported to also regulate food intake [64] and stress response [42], we cannot exclude the possibility that RFRP-3 neurons may regulate female reproduction indirectly through metabolicand stress-regulated mechanisms.…”