Kisspeptin and Metabolism - Influence on Energy & Appetite Regulation

Spanning from brown fat mitochondria to the suprachiasmatic nucleus' circadian machinery, kisspeptin is a metabolic polyglot—converting shifts in glucose, leptin, thyroid hormone and circadian timing into GnRH pulsatility and conversely guiding hunger, thermogenesis and insulin response. GPR54 is also located on pancreatic β-cells, liver sinusoids and adipose tissue-resident macrophages, so one and the same amidated peptide fragment can act as an endocrine currency to exchange energy solvency between organs. When under nutrient-rich conditions, elevated leptin and insulin can direct the translocation of histone modifiers to the Kiss-1 promoter and upregulate peptide expression, thus ensuring recovery of GnRH pulse frequency and LH secretion once sufficient metabolic reserves have been met. In the fasting or stress state, glucocorticoid-responsive elements repress Kiss-1 transcription, thereby pulling the excitatory plug on GnRH neuron drive to conserve caloric resources for survival rather than reproduction. In peripheral organs, kisspeptin-54 increases the expression of uncoupling proteins in brown fat, potentiates glucose-stimulated but self-limiting insulin secretion in the pancreas, and induces polarization of adipose tissue macrophages towards an M2 anti-inflammatory phenotype, all of which results in a metabolic signature of high energy expenditure, better glucose tolerance and lower visceral fat. Since this peptide is short-lived in circulation due to peptidases, these are a transient and self-limiting sequence of effects, and so physiologically provides a way to re-align energy balance with fertility intent without the compensatory overshoot of sympathomimetic or exogenous hormone cocktails. Kisspeptin is being trialled clinically to time the return of ovulatory cycles to shift workers whose circadian misalignment has thrown off their menstrual cycle, and to synergise with mitochondrial uncouplers in order to reverse the metabolic syndrome-associated hypogonadotropic, hyper-insulinaemic state. In the future, adaptive trials are underway to see if computer-guided micro-infusions responsive to real-time glucose or core-body-temperature rhythms can synchronise metabolic cycles with reproductive intent, thus redefining kisspeptin as a metabolic conductor that is aware of system-wide networks.

Fig. 1 Schematic representation of the interaction of systemic metabolic cues with Kisspeptin (KP), orexigenic, and anorexigenic neurons: metabolic cues are secreted by metabolic organs in responses to alterations in metabolic status.^1,6

Kisspeptin and Energy Balance

Energy homeostasis is now considered as an oscillatory dialogue between central and peripheral pacemakers which has to be 'entrained' by reproductive needs. Kisspeptin is at the crossroads of these interactions. Arcuate kisspeptin neurons in the hypothalamus co-express leptin and insulin receptors, and a decrease in adiposity or an increase in ghrelin tone down peptide synthesis, effectively disinhibiting GnRH neurons (in order to preserve scarce energy for survival). By contrast, re-feeding causes a rise in leptin and insulin, which recruit histone acetyltransferases to the Kiss-1 promoter, thus re-establishing peptide synthesis and subsequently restoring pulsatile LH secretion, once an adequate metabolic state is reached. These neurons also project to POMC and AgRP cells, shifting the satiety–hunger balance towards satiety without triggering anhedonia which is associated with acute anorexigenic stimulation. In peripheral tissues, kisspeptin receptors are present in brown and white adipose tissue. Their stimulation in these tissues increases the number of uncoupling proteins and enhances lipid oxidation, thus increasing energy expenditure and limiting ectopic lipid storage. In pancreatic islets, kisspeptin-54 potentiates glucose-stimulated insulin secretion in a Gαq-Ca²⁺ dependent manner. However, this is transient as the same stimulus also promotes insulin clearance through the hepatic receptor, thus precluding a hyper-insulinaemic lock-in effect. As such, this central–peripheral pleiotropy is able to re-entrain dysfunctional energy rhythms, such as in functional hypothalamic amenorrhoea, caloric-restriction-induced infertility or post-bariatric surgery hypogonadism.

Role in Hypothalamic Regulation

Kisspeptin's primary function is as a signal of energetic solvency on a whole body scale. Arcuate kisspeptin neurons are targets of dense monosynaptic innervation by AgRP/NPY and POMC/CART nerve terminals for integration of the net energy status of the organism. Negative energy balance causes high AgRP tone to hyperpolarise kisspeptin cells via GABA_A receptors, inhibit peptide secretion and increase GnRH interpulse intervals, a pause in neuroendocrine output that tempers the energetic expense of ovulation. Feeding reverses this effect: increased leptin depolarises these neurons via JAK2-STAT3 signalling, insulin recruits PI3K to increase kisspeptin translation and GnRH pulse frequency, such that the organism's reproductive capacity is synchronised with its metabolic state. Suprachiasmatic nucleus efferents release glutamate onto kisspeptin dendrites to circadian gate kisspeptin output, limiting pulsatile GnRH release to the waking period of the day when foraging success is highest. Temporally coupling GnRH/LH surge to the circadian period of maximal energy acquisition reduces the risk of luteal-phase insufficiency. Optogenetic inactivation of kisspeptin neurons disrupts circadian feeding behaviour and causes weight gain in the presence of isocaloric diet, which implicates kisspeptin in the modulation of energy expenditure via this circadian output.

Metabolic Pathway Interactions

In addition to regulating the HPG axis at the hypothalamic level, kisspeptin is expressed by the brown adipocytes, hepatocytes, and pancreatic β-cells and can exert peripheral effects on metabolism. Binding of kisspeptin to its receptor in brown adipocytes upregulates uncoupling protein expression and mitochondrial biogenesis. This effect has the net result of increased lipid oxidation and thermogenesis and a relative shift in substrate use to fatty acids, but this effect occurs without the side-effect of tachycardia that is normally associated with β-adrenergic stimulation. Kisspeptin receptor signaling in the liver inhibits the expression of gluconeogenic enzymes and promotes glycogen storage, the net result of which is reduced fasting glucose levels without the side-effect of hyper-insulinaemia normally observed in response to hypoglycemic interventions. In the pancreatic islet, kisspeptin-54 stimulates glucose-induced insulin secretion through a Gαq-dependent calcium signaling pathway. However, the resulting peak in circulating insulin is blunted by the effect of kisspeptin to also increase insulin clearance from the circulation by promoting hepatic endocytosis, maintaining pulsatility in circulating insulin, and avoiding lipotoxicity. In adipose tissue, kisspeptin causes M2 polarization of macrophages to an anti-inflammatory phenotype which results in decreased local cytokine levels which may also affect insulin sensitivity. The net result of these cellular actions is a metabolic phenotype that is characterized by increased glucose tolerance, higher energy expenditure and decreased visceral fat. Kisspeptin pulsatile administration is being investigated in order to restore the hypogonadotropic, hyper-insulinaemic state without the side-effect of weight gain observed after exogenous gonadotropin administration, which would be more physiologically congruent with the desired effect of improving metabolic infertility.

Circadian and Seasonal Energy Encoding via Kisspeptin

Additional data suggests kisspeptin as a circadian transducer of reproductive effort, linked to photic and metabolic seasonality. Clock genes in the SCN drive daily rhythms in Kiss-1 expression so that peptide release is maximal at time of daily foraging period. This time-gating mechanism excludes energetically expensive LH surges during the sleep-fasting period when liver glycogen is low. In seasonal breeders, decreasing photoperiod suppresses kisspeptin expression, increasing the GnRH interpulse interval and inducing reversible gonadal regression as a way to conserve energy. Initial studies in humans have been carried out to investigate if time-controlled kisspeptin infusions could be used to replicate these endogenous rhythms and reverse infertility in shift-workers where a circadian misalignment inhibits menstrual cycle regularity. This form of chronotherapy works to counteract reproductive dysfunction by resynchronizing endogenous metabolic clocks rather than by supplying constant exogenous hormones.

Appetite Regulation Research

Emerging evidence has suggested kisspeptin may be a pleiotropic neuropeptide that can connect reproductive neuroendocrinology and ingestive behavior, however, the specific effects are dependent on the direction. Administration of intraperitoneal kisspeptin-10 in mice causes a decrease in nocturnal food intake, meal frequency and eating rate and increase in insulin, leptin and resistin. In contrast, kisspeptin receptor knockout mice show a female-specific phenotype of decreased food intake and a slow progression of weight gain over time. This suggests that kisspeptin may have an orexigenic function due to the absence of endogenous peptide tone. In humans, intravenous kisspeptin administration at a dose that is sufficient to cause LH release did not affect self-reported hunger or fullness, or actual food intake in lean men or obese women. There was also no change in limbic activation in response to images of food using fMRI, and therefore did not demonstrate the same anorexigenic effects as in rodents. The differences may be due to the mode of administration. Central administration of kisspeptin-10 in animals can cause anorexigenic responses through effects on POMC and NPY neurons. In humans, peripheral infusion may not be able to enter the brain at large concentrations due to rapid clearance. The effects of intravenous kisspeptin have also been shown to be dependent on time. In male rats, a single injection causes anorexigenic effects. However, with daily injections for several days, the effect is lost. These data suggest that kisspeptin is a conditional modulator of appetite and ingestive behavior, and that the effects are dependent on sex, route, and chronicity and also on baseline metabolic state.

Studies Linking Kisspeptin to Food Intake

Initial studies in rodents had reported that acute central injection of kisspeptin-10 is sufficient to decrease dark-phase food intake in both male and female animals. This is associated with a reduction in both meal number and meal eating rate. Critically, the reduction in food intake is maintained even when animals are isocalorically pair fed and are not losing weight due to locomotor hyperactivity, thus, this anorexic phenotype is representative of a suppression of ingestive drive. Mechanistically, when hypothalamic slices are exposed to kisspeptin, POMC neurons are excited, and NPY cells are inhibited. This imbalance shifts the melanocortin system towards satiety. In the periphery, intraperitoneal kisspeptin injection decreases cumulative food intake and increases respiratory quotient in mice. The latter effect is consistent with a relative preference for carbohydrate oxidation over lipid oxidation and is, thus, reflective of an insulin-anabolic state. In a genetic model, female kisspeptin receptor knockout mice are hypophagic and exhibit increased adiposity despite eugonadal status, thus, these data suggest that tonic kisspeptin signalling is necessary for the maintenance of appetite. In humans, results are mixed. In a randomised, placebo-controlled, crossover study of healthy-weight males, intravenous kisspeptin infusion did not alter subjective hunger ratings or total energy intake, despite a robust rise in LH. The same group performed an analogous study in women with obesity and found no differences in ad-libitum meal size, pre-prandial ghrelin or post-prandial insulin responses. The lack of translatability of the rodent phenotype to humans has been ascribed to the differential blood–brain barrier permeability in rodents and humans and to the short half-life of kisspeptin-10 in human circulation. Overall, the data suggest that kisspeptin may have the ability to suppress food intake under supraphysiological central administration or in a genetically modified state, but, when peripherally delivered at physiologic doses, it does not appear to affect human ingestive behavior.

Potential Implications in Obesity Research

Kisspeptin acts at different levels in the metabolic system. Kisspeptin secretion in the hypothalamus is repressed by decreasing leptin and increasing ghrelin, creating a direct molecular connection between body fat and the desire to reproduce. On the other hand, kisspeptin neurons synapse on POMC and AgRP neurons and release glutamate and neuropeptide which directly stimulate the satiety inducing melanocortin system and inhibit NPY, the appetite increasing neuropeptide, in these neurons, respectively, to adjust the microstructure of feeding. In adipose tissue, kisspeptin receptor is coupled with Gαq, which increases the phosphorylation of hormone sensitive lipase and stimulates the release of fatty acids, while also upregulating the expression of uncoupling protein, leading to increased thermogenesis without systemic increases in catecholamines. Islet cells of Langerhans express both GPR54 and components in its Gαq signaling cascade. Activation of GPR54 promotes glucose-induced insulin secretion, but also increases insulin degradation due to the increased expression of GPR54 in hepatocytes that cause increased receptor-mediated endocytosis of insulin. Thus, insulin signaling is preserved in pulsatile form, which may prevent lipotoxicity. In the setting of chronic obesity, the interaction between leptin and kisspeptin is diminished. Due to leptin resistance, kisspeptin neurons are less activated. Kisspeptin receptor expression is also decreased, possibly due to endoplasmic reticulum stress. In this case, metabolic dysfunction may further decrease reproductive signaling. Pulsatile injections of kisspeptin are currently being investigated in order to increase leptin sensitivity and normalize circadian feeding in obesity.

Broader Metabolic Research Opportunities

Kisspeptin is emerging as a systemic metabolic regulator from a reproductive neuropeptide, with actions ranging from pancreatic β-cell stimulus–secretion coupling to brown-adipose thermogenic tone. The initial loss-of-function studies in rodents showed that global deletion of kisspeptin signaling, while gonadal steroidogenesis is maintained, can lead to adult-onset obesity and glucose intolerance, and is therefore a primordial regulator of energy balance that is separable from its hypothalamic–pituitary–gonadal effects. The molecular mechanism involves a Gαq-phospholipase C–Ca2+ axis within the islet cells to enhance glucose-induced insulin release. There is also a hepatic–pancreatic feed-forward and feed-back loop that limits excessive insulin release; after stimulation by glucagon, hepatic KISS1 is expressed, which then restrains exaggerated insulin output, and thereby can prevent post-prandial hypoglycemia. Activation of the receptor in adipose tissue increases uncoupling-protein expression and mitochondrial content, which favors lipid oxidation over glucose oxidation, and it enhances thermogenesis without inducing tachycardia (an adverse effect of sympathomimetic drugs). These diverse pathways place kisspeptin in a physiological position to re-align energy expenditure with reproductive fitness in a range of conditions including type-2 diabetes, polycystic ovary syndrome, and caloric restriction-induced infertility. Indeed, clinical studies are now being allowed to proceed that examine pulsatile administration of kisspeptin as a steroid-sparing intervention to restore glycaemic control while also re-establishing ovulatory cyclicity, and thus move the field beyond simply descriptive physiology into therapeutic proof-of-concept.

Fig. 2 Peripheral metabolic regulation by kisspeptin.^2,6

Kisspeptin in Diabetes and Endocrine Disorders

Kisspeptin also appears to have metabolic effects. Diabetes mellitus, both autoimmune and metabolic, is becoming understood as a disease of disordered pulsatility (of insulin, glucagon or incretin spikes) rather than deficiency per se. Kisspeptin could influence this in two complementary ways. One: the pancreatic islets transcribe both KISS1 and KISS1R; exogenous administration of kisspeptin-54 causes an increase in glucose stimulated insulin secretion, through a Gβγ dependent mechanism that increases intracellular calcium; however, the insulin spike is then abrogated because the peptide also causes the liver to clear insulin from the bloodstream faster, protecting pulsatile kinetics and the lipotoxicity they prevent. Two: a liver-pancreas endocrine axis has been characterized in which glucagon causes the liver to produce KISS1 (through cAMP–PKA–CREB signalling), the kisspeptin it releases entering the portal vein and suppressing further insulin secretion, to form a negative-feedback loop which prevents hyperinsulinaemia after meals. Pancreatic kisspeptin content is nearly eliminated along with β-cell mass in streptozotocin-induced type-1 diabetes, while type-2 models have both higher hepatic KISS1 and lower islet KISS1R, uncoupling the feedback brake and causing insulin hypersecretion. Reinstating kisspeptin pulsatility in these models normalizes glucose fluctuations without causing hypoglycaemia, in contrast to the static hyperinsulinaemia caused by sulfonylureas. In adipose tissue, kisspeptin receptor activation polarizes macrophages towards the anti-inflammatory M2 phenotype, reducing the local cytokine environment that disrupts insulin signalling. Clinical trials in humans are underway to see if subcutaneous administration of low-dose kisspeptin infusions can improve glycaemic variability in adults with long-standing type-2 diabetes who are otherwise poorly controlled despite incretin-based medications.

Future Research Directions

Kisspeptin is undergoing further investigation in trials to modulate its influence in type 2 diabetes, which is moving away from conventional isolated organ pharmacology and into a more network conscious, rhythm-based approach. Trial designs are being developed where the peptide is dose-adjusted in real time via continuous monitoring of glucose or even body temperature, with the aim of entraining insulin oscillations to fit into a more circadian based pattern, similar to natural metabolic oscillations. There are also approaches to begin to look at the bioactivity of different isoforms, with evidence that while the amidated, longer kisspeptin-54 seems to engage the GPR54 outside the brain in a more permissive role, increasing insulin clearance, the shorter fragments may also enter the brain and suppress appetite. This has led to exploration of dual-route delivery to make use of the different kinetics. A next stage of exploration is combining kisspeptin with GLP-1 mimetics, as the Ca2+-dependent insulin potentiation could work in synergy with the cAMP dependent effect of GLP-1 analogues, and might allow for lower doses of each whilst maintaining glycaemic control and reducing GI side effects. There are some longer-term safety questions being asked about kisspeptin that could affect its application, including whether or not chronic exposure to the peptide could lead to desensitization of the receptors on the islet, or disrupt the thyroid axis, and these will likely be monitored in integrated endocrine tests as part of upcoming phase-II trials. There is also investigation into epigenetic plasticity and whether early life metabolic insult might re-sculpt the neuronal enhancers for kisspeptin, and in doing so set a child up with a trans-generational risk of diabetes as well as sub-fertility. If these findings are proven, it would make kisspeptin not just a therapeutic target, but also a biomarker for metabolic programming and a guide for personalised lifestyle or drug treatment to restore physiologic oscillation.

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Kisspeptin has been shown to influence hypothalamic pathways, impacting energy expenditure, appetite regulation, and metabolic hormone control.

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