Estrogenic regulation of reproduction and energy homeostasis by a triumvirate of hypothalamic arcuate neurons

Abstract

Pregnancy is energetically demanding and therefore, by necessity, reproduction and energy balance are inextricably linked. With insufficient or excessive energy stores a female is liable to suffer complications during pregnancy or produce unhealthy offspring. Gonadotropin-releasing hormone neurons are responsible for initiating both the pulsatile and subsequent surge release of luteinizing hormone to control ovulation. Meticulous work has identified two hypothalamic populations of kisspeptin (Kiss1) neurons that are critical for this pattern of release. The involvement of the hypothalamus is unsurprising because its quintessential function is to couple the endocrine and nervous systems, coordinating energy balance and reproduction.Estrogens, more specifically 17β-estradiol (E 2 ), orchestrate the activity of a triumvirate of hypothalamic neurons within the arcuate nucleus (ARH) that govern the physiological underpinnings of these behavioral dynamics. Arising from a common progenitor pool, these cells differentiate into ARH kisspeptin, pro-opiomelanocortin (POMC), and agouti related peptide/neuropeptide Y (AgRP) neurons. Although the excitability of all these subpopulations is subject to genomic and rapid estrogenic regulation, Kiss1 neurons are the most sensitive, reflecting their integral function in female fertility. Based on the premise that E 2 coordinates autonomic functions around reproduction, we review recent findings on how Kiss1 neurons interact with gonadotropin-releasing hormone, AgRP and POMC neurons, as well as how the rapid membrane-initiated and intracellular signaling cascades activated by E 2 in these neurons are critical for control of homeostatic functions supporting reproduction. In particular, we highlight how Kiss1 and POMC neurons conspire to inhibit AgRP neurons and diminish food motivation in service of reproductive success.

High sucrose consumption decouples intrinsic and synaptic excitability of AgRP neurons without altering body weight

“…Female mice were also resistant to weight gain following SucrW consumption (Fig. S2A) and based on previous studies, we predict dissimilar metabolic and synaptic mechanisms that will require future investigation [31,[60][61][62][63]. NMR for body composition revealed no difference in fat mass in SucrW mice compared to NDW controls but did have a decrease in lean mass (Fig.…”

Plasma Metabolomic Profiling after Feeding Dried Distiller’s Grains with Solubles in Different Cattle Breeds

“…Testosterone is also one of the two initiation products of the GnRH secretion pathway, which indirectly inhibits the activity of the kisspeptins (Kiss1) metastasis suppressor and affects the synthesis of Kiss1. Kiss1 can strongly depolarize GnRH neurons, thus affecting GnRH synthesis [ 42 ]. GnRH is synthesized in the hypothalamus of vertebrates and is a key endocrine regulator that drives the hypothalamus–pituitary–gonad axis and ultimately activates the reproductive endocrine network.…”

CRISPR/SaCas9 mutagenesis of stromal interaction molecule 1 in proopiomelanocortin neurons increases glutamatergic excitability and protects against diet-induced obesity

“…Hence, the output of Kiss1 ARH neurons excites the anorexigenic POMC neurons and inhibits the orexigenic AgRP neurons. Therefore, Kiss1 ARH neurons appear to be an integral part of an anorexigenic circuit in the hypothalamus [ 7 , 70 , 71 ] [ 72 ], which funnels through TRPC 5 signaling in POMC neurons. Besides the glutamatergic projections from the local ARH (kisspeptin) neurons there are glutamatergic inputs from the ventromedial nucleus that are highly regulated by energy states [ [73] , [74] , [75] , [76] , [77] ] that may also signal via mGluR1/5 and be similarly augmented by STIM1 downregulation.…”