Introduction
Kisspeptin, a peptide encoded by the Kiss1 gene, and its receptor, KISS1R, have been identified as crucial regulators of reproduction. Recent research suggests that kisspeptin signaling also plays a significant role in metabolism and energy balance. This article explores the emerging evidence for kisspeptin's involvement in regulating various metabolic parameters, including body weight, energy expenditure, adiposity, food intake, glucose metabolism, and thermoregulation.
Kisspeptin and Reproduction: A Well-Established Role
Kisspeptin and its receptor, KISS1R, have been established as critical regulators of reproduction over the past two decades. Mutations in the Kiss1r and Kiss1 genes in humans and mice lead to infertility, impaired puberty, and low levels of gonadotropins and sex steroids. Kisspeptin stimulates the secretion of gonadotropin-releasing hormone (GnRH), which controls the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Neural kisspeptin regulates the pulsatile and surge modes of GnRH and LH release, which are essential for reproductive function. Metabolic factors and conditions regulate kisspeptin neurons, integrating peripheral metabolic cues to adjust reproductive function according to energy status.
Kisspeptin and Metabolism: A Bidirectional Relationship
The relationship between kisspeptin/KISS1R and metabolism and energy balance is bi-directional. Metabolic cues regulate the kisspeptin system, and kisspeptin signaling affects metabolism and energy balance via central (hypothalamic) and peripheral sites of action. This article focuses on the emerging actions of kisspeptin signaling on metabolism and energy balance, including modulation of body weight, adipose tissue, feeding and energy expenditure, insulin secretion and glucose homeostasis, and thermoregulation.
Expression of Kisspeptin and its Receptor in Metabolically-Relevant Tissues
Both Kiss1 and Kiss1r are expressed in metabolically-relevant peripheral tissues, including white and brown adipose tissue, the liver, and the pancreas, suggesting possible actions on these tissues or involvement in their physiology. Kiss1r is expressed in a wide variety of target tissues including the brain, liver, pancreas, adipose, BAT, gonad, and placenta. Kisspeptin signaling has been shown to affect several of these tissues, although for most peripheral effects the endogenous physiological source of kisspeptin is unknown. It is not clear if there are also autocrine/paracrine effects of kisspeptin acting on the same peripheral tissue that synthesized it. The role of kisspeptin synthesis and possible secretion from many peripheral tissues has not yet been studied.
Kisspeptin's Influence on Body Weight: Evidence from Animal Models
One of the earliest indications that kisspeptin might affect metabolism and energy balance was the observed effects of global Kiss1r knockout (KO) on body weight (BW) and energy expenditure in rodent models. Adult Kiss1r KO female mice displayed a large increase in BW versus WT female littermates, emerging around 10-12 weeks of age, with Kiss1r KO females weighing a notable 30% more than controls by 18 weeks of age. This elevated BW in females was further confirmed in a different mouse line: Zp3-Cre/Kiss1rfl/fl (whole body Kiss1r KO) females displayed increased BW and elevated adiposity similar to the original global Kiss1r KOs. In contrast, adult male Kiss1r KO mice did not have increased BW compared to WT control males. However, other studies have reported a reduced BW in Kiss1r KO males at younger ages up until 6 weeks of age or between 9 and 12 weeks of age. Studies of Kiss1 KO mice (knocking out the kisspeptin gene) have either found no difference in BW in young adult males and females, or slightly lower BW in younger animals ≤8 weeks old.
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Kiss1r KO females also showed a 100% (2-fold) increase in fat mass and a small but significant decrease in lean mass, indicating that their BW phenotype was due entirely to increased adiposity. Fat mass was also higher in Kiss1r KO males though to a smaller magnitude of 50% versus control males. However, Kiss1r KO males also displayed a greater decrease in lean mass compared to KO females (25% versus 6%), potentially explaining the lack of a detectable overall BW increase in the males despite their increased adiposity. Accordingly, leptin levels were greatly increased by 450% in female Kiss1r KOs but only elevated by 300% in males, though that is still a large increase.
Chronic i.c.v. kisspeptin treatment decreased BW in female rats. Cre-dependent silencing of kisspeptin neurons also induced increased BW in females, indicating that kisspeptin neurons could be a key component of the overall Kiss1r KO obesity phenotype. However, it is not clear from that study alone if the increased BW is due exclusively to diminished kisspeptin signaling or to reduced signaling by other co-transmitters.
Energy Expenditure and Food Intake: Unraveling the Mechanisms Behind Weight Changes
Kiss1r KO mice display decreased feeding, despite ultimately becoming very overweight. The increased BW is not due to increased energy intake but rather occurs in spite of decreased energy intake. Kiss1r KOs have decreased energy expenditure. Adult Kiss1r KO females on a normal diet have dramatically reduced locomotor activity, oxygen consumption (VO2), and carbon dioxide production (VCO2), resulting in a decreased respiratory exchange rate (RER) and energy expenditure, especially during the dark phase when mice are more active. The female Kiss1r KO obesity phenotype stems primarily from reduced energy expenditure. The impaired metabolic phenotypes in global Kiss1r KO females were further confirmed in the Zp3-Cre/Kiss1rfl/fl mouse line in which females similarly displayed hypogonadism, increased BW, elevated adiposity and leptin, and reduced dark phase energy expenditure. A recent study in male rats found that a single i.c.v. injection of kisspeptin (3 nmol Kp-10) reduced RER, the opposite of what might be expected from the female Kiss1r KO results.
Kisspeptin and Adiposity: An Adipokine Role?
Kisspeptin is an important adipokine involved in regulating energy homeostasis and body weight. Plasma concentrations of kisspeptin were significantly higher in obese subjects. An increased mass of adipose tissue could be responsible not only for increased kisspeptin secretion but also for the increased ENA-78 secretion. Kisspeptin may act as an adipokine more than a neuropeptide in obese population. Serum kisspeptin is significantly elevated in obese individuals. Serum ENA-78 concentration was also significantly elevated in obese individuals; this elevation could be due to the increased mass of adipose tissue and chronic inflammation caused by obesity.
Increased mass of adipose tissue is responsible for increased kisspeptin. Kisspeptin could act more as an adipokine in obese people than as a neuropeptide. Obesity alters the expression of kisspeptin and its receptor, and kisspeptin in turn regulates the glucose homeostasis and alters the body weight.
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Kisspeptin and Glucose Metabolism: Implications for Diabetes
Kiss1r KO females showed higher fasted basal glucose levels and greatly impaired glucose tolerance in a glucose tolerance test (GTT) relative to WT and Het females. In vitro and in vivo kisspeptin treatment augments glucose-induced insulin secretion, supporting a possible role in pancreatic β cell function, which could potentially underlie the impaired glucose tolerance we observed in Kiss1r KO females.
Kisspeptin's Mechanism of Action: Central vs. Peripheral Effects
The underlying mechanisms of the obesity and glucose impairment in Kiss1r KO mice is unknown and could reflect impaired kisspeptin signaling in the brain and/or periphery. In the brain, kisspeptin neurons innervate some anorexigenic POMC and orexigenic NPY neurons. However, the reduced (rather than increased) feeding in our obese Kiss1r KO mice argues against this simple explanation of dysregulated NPY and POMC and suggests that multiple pathways might be affected. Alternatively, or concurrently, the metabolic and diabetic phenotypes in Kiss1r KO mice may arise due to peripheral absence of kisspeptin signaling, as KISS1R is found in adipose, liver, stomach, and pancreas. Different phenotypic parameters in Kiss1r KO mice (e.g., adiposity, locomotion, and glucose homeostasis) may independently reflect impaired kisspeptin signaling in different target pathways/tissues. Moreover, whether the diabetic or metabolic phenotypes occur independently, or as indirect or secondary consequences of the obesity, remains to be determined.
Kisspeptin and other factors
Kisspeptin stimulates growth hormone release by utilizing neuropeptide Y pathways and is dependent on the presence of ghrelin in the Ewe.
Kisspeptin in Humans: Limited Evidence and Future Directions
The few studies on patients with KISS1 and KISS1R mutations have not yet reported an obesity phenotype. However, it is difficult to conclude anything yet because these studies were generally performed in young patients, before one might expect adulthood obesity to emerge (based on our mouse data), and body composition, metabolism, and glucose tolerance were not assessed.
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