Emerging roles for kisspeptin in metabolism

Abstract

Kisspeptin, a neuropeptide hormone, has been firmly established as a key regulator of the hypothalamic-pituitary-gonadal axis and mammalian reproductive behaviour. In recent years, a growing body of evidence has emerged suggesting a role for kisspeptin in regulating metabolic processes. This data suggest that kisspeptin exerts its metabolic effects indirectly via Chioma Izzi-Engbeaya (MBBS PhD MRCP) is an Imperial-BRC Research Fellow at Imperial College London and a Consultant Endocrinologist at Imperial College Healthcare NHS Trust. Her research focuses on the hormonal control of metabolism and reproduction. Her work demonstrated for the first time in humans that kisspeptin enhances insulin secretion. Additionally, she is pioneering the use of novel techniques such as thermal imaging to study brown adipose tissue activation and the use of aptamer-based hormone measurement. Waljit Dhillo (MBBS PhD FRCP) is a Professor of Endocrinology and Metabolism at Imperial College London and a Consultant Endocrinologist at Imperial College Healthcare NHS Trust. His research has focused on understanding the neuroendocrine mechanisms which are important in the regulation of food intake. Furthermore, his recent pioneering translational research has identified kisspeptin as a novel therapeutic target for patients with infertility and NK3 receptor antagonists as a new treatment for post-menopausal flushing.

Endogenous Androgens Diminish Food Intake and Activation of Orexin A Neurons in Response to Reduced Glucose Availability in Male Rats

“…Kisspeptin neurons in the arcuate nucleus are involved in the negative feedback regulation of the HPG axis and express androgen receptors [ 32 , 33 ]. Kisspeptin has been shown to enhance the expression of orexigenic NPY and attenuate the expression of anorexigenic POMC [ 32 , 34 , 35 , 36 ], and the glucosensitive NPY neurons are known to connect reciprocally with orexin A neurons [ 37 , 38 , 39 ]. These findings suggest that the enhanced responses of feeding and orexin A neuron activity to reduced glucose availability in orchiectomized rats are mediated by increased NPY, induced by a lower level of androgens.…”

“…The enhanced c-Fos expression in the dorsomedial Arc by orchiectomy in the present study suggests a possibility that reduced androgen enhances the NPY neurons by stimulating the kisspeptin neurons. However, kisspeptin has also been reported to excite POMC neurons and inhibit NPY neurons [ 32 , 34 , 40 ], and intracerebroventricular kisspeptin reduces food intake [ 41 ], suggesting that kisspeptin has anorexigenic properties. In contrast, some studies reported that an intracerebroventricular injection of kisspeptin had no effect on food intake [ 32 , 42 ].…”

Sexual Dimorphism in Kisspeptin Signaling

“…Recent studies also suggest that KP neurons in ARC nuclei regulate lactation [ 171 ], appetite and growth hormone release [ 172 ]. Findings in whole body knockout models of KPR (KPR KO ) suggest that KP-signaling plays an important role in energy expenditure, food intake and body weight gain and this is sexually dimorphic [ 173 , 174 ]. KPR KO female mice gained body weight and developed impaired glucose tolerance, but the KPR KO male mice suffered loss of body weight due to a suppression of feeding [ 174 , 175 ].…”

“…Data from in KPR KO mice suggest that KP-signaling may impact energy expenditure, food intake and body weight in a sexually dimorphic manner [ 173 , 174 ]. The metabolic and diabetic phenotypes in KPR KO mice could be due to reduced pancreatic β-cell function and the absence of peripheral KP-signaling [ 202 , 203 ].…”

“…The metabolic and diabetic phenotypes in KPR KO mice could be due to reduced pancreatic β-cell function and the absence of peripheral KP-signaling [ 202 , 203 ]. It can also be mediated by a direction action of KPs on the KPR in the brain, pancreas, and brown adipose tissues or via GPN induction [ 173 , 175 ]. Understanding the sexually dimorphic phenotype of KPR KO females may also give insight into polycystic ovarian syndrome, a common reproductive and metabolic syndrome seen in 10% of all reproductive aged women [ 204 ].…”