PI3K signalling in leptin receptor cells: Role in growth and reproduction

Abstract

Nutrition and growth are important signals for pubertal development, although how they are perceived and integrated in brain circuits has not been well defined. Growth hormones and metabolic cues both recruit phosphatidylinositol 3‐kinase (PI3K) signalling in hypothalamic sites, although whether they converge into the same neuronal population(s) is also not known. In this review, we discuss recent findings from our laboratory showing the role of PI3K subunits in cells directly responsive to the adipocyte‐derived hormone leptin in the coordination of growth, pubertal development and fertility. Mice with deletion of PI3K p110α and p110β catalytic subunits in leptin receptor cells (LRΔα+β) have a lean phenotype associated with increased energy expenditure, locomotor activity and thermogenesis. The LRΔα+β mice also show deficient growth and delayed puberty. Deletion of a single subunit (ie, p110α) in LR cells (LRΔα) causes a similar phenotype of increased energy expenditure, deficient growth and delayed pubertal development, indicating that these functions are preferably controlled by p110α. The LRΔα mice show enhanced leptin sensitivity in metabolic regulation but, remarkably, these mice are unresponsive to the effects of leptin on growth and puberty. PI3K is also recruited by insulin and a subpopulation of LR neurones is responsive to i.c.v. insulin administration. Deletion of insulin receptor in LR cells causes no changes in body weight or linear growth and induces only a mild delay in pubertal completion. Our findings demonstrate that PI3K in LR cells plays an essential role in growth and reproduction. We will also discuss the potential neural pathways underlying these effects.

Ginsenoside Rb1 as an Anti-Diabetic Agent and Its Underlying Mechanism Analysis

“…Insulin resistance is an abnormal physiological state and the main cause of type 2 diabetes (insulin-independent diabetes), meaning that target cells are not sensitive to insulin and require relatively more insulin to maintain normal blood glucose levels, which can be caused by abnormal structure of insulin, the abnormal binding of insulin receptors, insulin degradation, insulin receptor defects, metabolic signal transmission error, etc. Recently, the tendency of drug prescription for type 2 diabetics has moved from agents that stimulate insulin secretion toward agents that increase insulin sensitivity by activating the hepatic AMPK, PI3K, and Akt activity [12,14,15,16,69,70].…”

“…Recently, there has been a shift in the drugs prescribed for T2DM from agents that stimulate insulin secretion, such as sulfonylureas, towards agents that increase insulin sensitivity, such as biguanides (BGs) [7] and thiazolidinediones (SUs) [8,9,10]. These latter classes of drugs activate the hepatic adenosine monophosphate-activated protein kinase (AMPK) [11,12,13], phosphatidylinositol 3-kinase (PI3K), and protein kinase B (PKB/Akt) [14,15,16], stimulate fatty acid oxidation in an AMPK- and peroxisome proliferator activated receptor-α (PPAR-α)-dependent manner, and inhibit the interference with c-Jun amino-terminal kinases (JNKs) and insulin action activated by inflammatory cytokines and free fatty acids [17,18], all of which are new targets and new ways of reducing blood sugar, obesity, and diabetes symptoms.…”

Polycomb represses a gene network controlling puberty via modulation of histone demethylase Kdm6b expression

“…These leptin sensitive neurons project and make contacts with GnRH and KNDy neurons at the level of the ARC and median eminence, possibly affecting their activity through glutamate release 74 . Activation of growth factor and hormone receptors induce increased activity of several intracellular pathways including the phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), JAK/STAT and the MAPK pathways 75 – 80 . While the activation of the PI3K/AKT and MAPK pathways phosphorylate several PcG members, causing their dissociation from target regulatory regions 81 , 82 , the activation of PI3K/AKT and STAT pathways induce the phosphorylation of KDM6B 83 and increased K27-dependent demethylase activity.…”

Lin28 gene and mammalian puberty

“…The onset of puberty is also gated by body energy reserves and nutritional cues (Vazquez, Velasco, & Tena‐Sempere, 2019), and in which, the adipose hormone leptin is an essential signal to the hypothalamic GnRH pulse generator that there are sufficient energy stores in the adipose tissue for fertility to commence, which is necessary for the initiation of puberty (Ahmed, Ong, & Dunger, 2009; Biro, Khoury, & Morrison, 2006; Egan, Inglis, & Anderson, 2017). Leptin stimulates GnRH secretion by binding to the leptin receptor to activates several signaling pathways, including the 5′ adenosine monophosphate‐activated protein kinase (Roa et al, 2018; Xie et al, 2018), mammalian target of rapamycin (mTOR; Roa & Tena‐Sempere, 2010; Roa et al, 2009), phosphoinositide 3‐kinase (PI3K; Garcia‐Galiano, Borges, Allen, & Elias, 2019; Garcia‐Galiano et al, 2017; Nelson et al, 2017; Nguyen, Zacchi, Schulz, Moore, & Fortes, 2018).…”