Kisspeptin and RFRP3 modulate body mass in Phodopus sungorus via two different neuroendocrine pathways

Abstract

Many animals exhibit remarkable metabolic and reproductive adaptations to seasonal changes in their environment. When day length shortens, Djungarian hamsters (Phodopus sungorus) reduce their body weight and inhibit their reproductive activity, whereas the opposite occurs in springtime. These physiological adaptations are considered to depend on photoperiodic changes in hypothalamic genes encoding the peptides kisspeptin (Kp) and RFamide‐related peptide 3 (RFRP3) for the control of reproduction, as well as pro‐opiomelanocortin and somatostatin for metabolic regulation. The present study investigates the effect of Kp and RFRP3 on long‐term body weight regulation, aiming to establish whether metabolic and reproductive hypothalamic networks may interact during adaptation to seasonal physiology. We found that chronic central administration of both Kp and RFRP3 in short photoperiod‐adapted male Djungarian hamsters increased body weight, although via different pathways. The effect of Kp was dependent on testicular activity because castration prevented the body weight increase and was associated with an increase in pro‐opiomelanocortin and neuropeptide Y expression. On the other hand, the orexigenic effect of RFRP3 was associated with an increase in circulating insulin and leptin levels, although it had no effect on any of the hypothalamic metabolic genes investigated, and did not change circulating levels of sex steroids. Notably, neither Kp, nor RFRP3 altered female hamster metabolic parameters. Thus, using a rodent model exhibiting seasonal changes in reproduction and metabolism, the present study demonstrates that, in addition to its role in the central control of reproduction, Kp also participates in body weight control in a sex‐dependent manner via an anabolic action of testosterone. Conversely, RFRP3 affects body weight control in males mostly by acting on adiposity, with no overt effect on the reproductive system in both sexes.

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

“…Our finding is in contrast to earlier studies reporting an orexigenic effect of RFRP3 in the male rat 7,13 . Intriguingly, in a recent study in which we investigated the chronic (5 weeks) metabolic effect of a central continuous infusion of RFRP3 in SD‐adapted lean Djungarian hamsters, RFRP3 displayed an opposite sex‐dependent effect because it was able to restore feeding activity, bodyweight and levels of leptin and insulin in the male but not the female animals 50 . This latter finding is in line with a recent study reporting that long‐term alteration of the RFRP3 signalling (via genetic mutation of its receptor) affects male, but not female mouse metabolic activity 51 .…”

“…Yet, compared to the present study, these findings highlight another aspect of the biological effect of RFRP3 comprising the acute vs long‐term effects, indicating that the acute and chronic effects most probably involve different cellular mechanisms. The acute orexigenic effect of RFRP3 in female Djungarian hamsters and jerboas is associated with an increase in Npy expression (as shown in the present study, as well as reported previously 14 ), whereas the chronic orexigenic effect of RFRP3 in male Djungarian hamsters occurs with no apparent change in the expression of the metabolic genes Pomc , Npy and Somatostatin 50 …”

What can seasonal models teach us about energy balance?

“…Despite the extreme adaptations to short photoperiod that change the obese and diabetic-like phenotype of Djungarian hamsters into a lean phenotype, there is no clear picture on seasonal changes of blood glucose levels. While early measurements showed a significant reduction of blood glucose from approximately 130 mg/dL in long photoperiod to 80 mg/dL in short photoperiod (Bartness et al 1995), these results could not be confirmed in later studies and again, glucose values varied between 100 and 250 mg/dL after at least 12 weeks of short photoperiod adaptation (Garcia et al 2010, Samms et al 2015, Cázarez-Márquez et al 2019. In contrast, blood insulin levels have consistently been shown to decrease from approximately 5 ng/mL in long photoperiod conditions to 1 to 2 ng/mL in short photoperiod conditions (Korhonen et al 2008, Cázarez-Márquez et al 2019).…”

“…While early measurements showed a significant reduction of blood glucose from approximately 130 mg/dL in long photoperiod to 80 mg/dL in short photoperiod (Bartness et al 1995), these results could not be confirmed in later studies and again, glucose values varied between 100 and 250 mg/dL after at least 12 weeks of short photoperiod adaptation (Garcia et al 2010, Samms et al 2015, Cázarez-Márquez et al 2019. In contrast, blood insulin levels have consistently been shown to decrease from approximately 5 ng/mL in long photoperiod conditions to 1 to 2 ng/mL in short photoperiod conditions (Korhonen et al 2008, Cázarez-Márquez et al 2019). Tups and colleagues could additionally demonstrate a substantial downregulation of the insulin receptor in the hypothalamus of juvenile hamsters that had been exposed to short photoperiod for eight weeks (Tups et al 2006).…”

“…This often results in an early onset of ketonuria and glycosuria, associated with glucose levels even higher than 300 mg/dL (Herberg et al 1980). The documented blood glucose concentrations of healthy hamsters under long photoperiod conditions vary in a broad range between 70 and 250 mg/dL, although the majority of studies report mean values between 100 and 150 mg/dL (Vesely & Herberg 1981, Bartness & Clein 1994, Bartness et al 1995, Garcia et al 2010, Carlton & Demas 2017, Lewis et al 2017, Cázarez-Márquez et al 2019. At least to some extent, this high variability can be attributed to different gender, feeding state, sampling time point and measurement methods, which makes it impossible to report general seasonal or circadian systemic glucose profiles in this species.…”