Metabolic actions of kisspeptin signaling: Effects on body weight, energy expenditure, and feeding

Abstract

Kisspeptin (encoded by the Kiss1 gene) and its receptor, KISS1R (encoded by the Kiss1r gene), have well-established roles in stimulating reproduction via central actions on reproductive neural circuits, but recent evidence suggests that kisspeptin signaling also influences metabolism and energy balance. Indeed, both Kiss1 and Kiss1r are expressed in many metabolically-relevant peripheral tissues, including both white and brown adipose tissue, the liver, and the pancreas, suggesting possible actions on these tissues or involvement in their physiology. In addition, there may be central actions of kisspeptin signaling, or factors co-released from kisspeptin neurons, that modulate metabolic, feeding, or thermoregulatory processes. Accumulating data from animal models suggests that kisspeptin signaling regulates a wide variety of metabolic parameters, including body weight and energy expenditure, adiposity and adipose tissue function, food intake, glucose metabolism, respiratory rates, locomotor activity, and thermoregulation. Herein, the current evidence for the involvement of kisspeptin signaling in each of these physiological parameters is reviewed, gaps in knowledge identified, and future avenues of important research highlighted. Collectively, the discussed findings highlight emerging non-reproductive actions of kisspeptin signaling in metabolism and energy balance, in addition to previously documented roles in reproductive control, but also emphasize the need for more research to resolve current controversies and uncover underlying molecular and physiological mechanisms.

Keywords: Adipose; Body weight; Diabetes; Energy expenditure; Fat; Feeding; Food intake; GPR54; Insulin; KISS1; KISS1R; Kisspeptin; Metabolism; Obesity.

Fig. 1.

Summary of the phenotypes of various Kiss1r KO mouse models on bodyweight, fat mass, lean mass, and energy expenditure. Adult Kiss1r KOs are whole body (“global) Kiss1r KO mice examined around 4–5.5 months of age (Tolson et al., 2014; Tolson et al., 2016; Tolson et al., 2019; Velasco et al., 2019), while OVX Kiss1r KO mice were had their ovaries removed in before puberty or in young adulthood and then were studied 3–4 months later around 5 months of age (and compared to similarly OVX littermate controls). Adult Kiss1r-Tg mice (~4 months old) are whole body Kiss1r KO mice with KISS1R selectively re-expressed only in GnRH neurons, which restores normal reproductive function and gonadotropin/sex steroid levels (Velasco et al., 2019). BAT Kiss1r cKO mice (4–5.5 months old) have Kiss1r selectively knocked out from BAT (Ucp-1 cells) (Tolson et al., 2020). Zp3-Cre/Kiss1r^fl/fl mice (4–5.5 months old) are whole-body Kiss1r KO mice generated by breeding mice expressing Cre under the Zp3 promoter with Kiss1r^fl/fl mice, which results in global KO of the Kiss1r gene (Tolson et al., 2019).

Fig. 2.

The effects of kisspeptin signaling on adipose tissue in vivo (A) and in vitro (B). (A) Kiss1r KO females lacking kisspeptin signaling throughout the body display increased fat mass (white adipose tissue) (Tolson et al., 2014; Tolson et al., 2016; Tolson et al., 2019; Velasco et al., 2019) but no difference in BAT weight (Tolson et al., 2020). However, Kiss1r KO females have decreased expression of the BAT genes Prdm16, Cox8b, and Ucp1 (Tolson et al., 2020). In contrast, BAT Kiss1r cKO females have decreased overall fat mass (white adipose tissue) and increased Cox8b expression in BAT, with normal BAT weight (Tolson et al., 2020). (B) Effects of Kp-10 administration in vitro in 3 T3-L1 cells and cultured male rat adipocytes. Kisspeptin decreased lipogenesis, adipogenesis, and 3 T3-L1 cell proliferation while increasing lipolysis, indicating that kisspeptin may inhibit lipid accumulation (Pruszyńska-Oszmałek et al., 2017), and could explain, in part, fat mass accumulation in Kiss1r KO mice lacking endogenous kisspeptin signaling.

Fig. 3.

The effects of kisspeptin signaling on food intake. (A) Global Kiss1r KO male and female mice show reduced food intake, especially during the dark phase when mice consume most of their food (Tolson et al., 2014; Velasco et al., 2019). Similarly, female Kiss1r-Tg mice (global Kiss1r KOs that have KISS1R rescued back into GnRH neurons), show decreased food intake (Velasco et al., 2019), though males do not. In contrast, selective knockout of Kiss1r from just BAT (BAT Kiss1r cKO) had no effect on daily food intake (Tolson et al., 2020). (B) Rodent studies of kisspeptin administration in vivo have found either no effect on feeding or an inhibition of food intake. More specifically, several studies administering kisspeptin peripherally found no effect on food intake (Izzi-Engbeaya et al., 2018; Stengel et al., 2011) whereas one study reporting a decrease in 24 h cumulative food intake after peripheral kisspeptin treatment (Dong et al., 2020). In contrast, most studies infusing kisspeptin centrally (i.c.v) report anorexigenic effects (decreased feeding) (Sahin et al., 2015; Saito et al., 2019; Stengel et al., 2011; Talbi et al., 2016); the anorexigenic effects in rodents generally required extended fasting before the refeeding period, except for one study reporting an anorexigenic effect in ad libitum fed male rats (Cázarez-Márquez et al., 2021). The anorexigenic effects of i.c.v. kisspeptin may be due to effects on hypothalamic hunger/satiety circuits (NPY and POMC neurons which are known to be regulated by arcuate kisspeptin neurons), although other brain areas may also be involved, and this still needs more investigation.

Fig. 4.

The effects of kisspeptin on glucose metabolism. (A) Effects of kisspeptin signaling on glucose tolerance. Adult global Kiss1r KO female mice, including gene trap Kiss1r KOs and Zp3-Cre/Kiss1r^fl/fl Kiss1r KOs, exhibit impaired glucose tolerance (Tolson et al., 2014; Tolson et al., 2019). Conditional knockout of Kiss1r from just the pancreas (Panc-Kiss1r cKOs) in male mice had no effect on glucose tolerance on a normal diet (consistent with Kiss1r KO males (Tolson et al., 2014)), but ameliorated the impaired glucose tolerance observed on HFD (Song et al., 2014). Conditional knockout of Kiss1r from just BAT (BAT Kiss1r cKOs) in female mice improved glucose tolerance (Tolson et al., 2020). Viral knockdown of Kiss1 in the liver (correlating with reduced circulating kisspeptin levels in the blood) of Lepr^db/db and HFD mice improves glucose tolerance with no effect on glucagon levels (Song et al., 2014). (B and C) The effect of exogenous kisspeptin administration on GSIS in vivo and in vitro. Multiple studies have come to different conclusions on the effect of kisspeptin on GSIS. Some studies report that kisspeptin decreases GSIS in vivo in mice (Huang et al., 2019; Song et al., 2014) and in vitro in NIT-1 cells (Huang et al., 2019), mouse pancreata (Silvestre et al., 2008), and isolated mouse islet cells (Song et al., 2014; Vikman & Ahrén, 2009). In contrast, other studies report kisspeptin increases GSIS in vivo in rats (Bowe et al., 2009), rhesus monkeys (Wahab et al., 2011), and men (Izzi-Engbeaya et al., 2018), and in vitro in mouse islet cells (Bowe et al., 2009; Bowe et al., 2012; Hauge-Evans et al., 2006; Schwetz et al., 2014), human islet cells (Bowe et al., 2012; Hauge-Evans et al., 2006; Izzi-Engbeaya et al., 2018), and porcine islet cells (Bowe et al., 2012). The discrepancy between these studies may be due in part to differences in kisspeptin or glucose concentrations used in the experiments, both of which tended to be lower in studies observing decreased GSIS after kisspeptin treatment.

Fig. 5.

Schematic showing possible metabolic actions of peripheral kisspeptin signaling. Blue dotted arrows show potential peripheral tissue sources of circulating kisspeptin the blood. Green arrows denote positive effects of kisspeptin on target tissues or cells, red arrows denote negative effects, while black arrows denote unknown/unstudied effects. Kiss1r is expressed in a wide variety of target tissues including the brain (not shown), liver, pancreas, adipose, BAT, gonad, and placenta (Brown et al., 2008; Hauge-Evans et al., 2006; Herbison et al., 2010; Kotani et al., 2001; Tolson et al., 2020). Kisspeptin signaling has been shown to affect several of these tissues, although for most peripheral effects the endogenous physiological source (specific tissue or cell type) of kisspeptin is unknown. Moreover, it is not clear if there are also autocrine/paracrine effects of kisspeptin acting on the same peripheral tissue that synthesized it. Indeed, the role of kisspeptin synthesis and possible secretion from many peripheral tissues has not yet been studied; for example, the pancreas and white adipose tissue both express Kiss1 and presumably synthesize kisspeptin (Brown et al., 2008; Cockwell et al., 2013; Dudek et al., 2016; Ohtaki et al., 2001; Tolson et al., 2020) but it is presently unclear where such kisspeptin acts or what its specific role(s) might be.