The role of leptin in the regulation of neuroendocrine function and CNS development

Abstract

Leptin, a hormone produced by adipocytes in proportion to fat stores, signals the sufficiency of energy reserves to the brain to control feeding and metabolism. Leptin represents a vital link between metabolic and neuroendocrine pathways, and adequate circulating leptin levels are required to permit the expenditure of energy on reproduction, growth, and other energy-intensive endocrine outputs. Leptin mediates its effects by acting upon a distributed network of CNS neurons that express the signaling form of the leptin receptor (LRb). Nutritional status early in development influences a lifelong metabolic program that modulates risk for diabetes, obesity and other elements of the metabolic syndrome. Recent evidence has demonstrated a number of important roles for leptin in the regulation of neural development and metabolic programming. In this review, we discuss leptin action, the neural circuits on which leptin acts, and our nascent understanding of how early leptin exposure may influence neural development and the predisposition to metabolic diseases.Keywords Leptin . Development . Metabolic syndrome . Brain Leptin and leptin actionThe discovery of leptin The story of leptin began half a century ago, with the identification of two spontaneously arising recessive alleles causing monogenic obesity and diabetes in mice-obese (ob) and diabetes (db) [1-3]. The ob/ob and db/db animals exhibit similar syndromes of hyperphagic obesity with prominent diabetes and endocrine dysregulation reminiscent of the fasting response (hypothalamic hypogonadism, decreased growth, decreased thyroid function, increased glucocorticoids, etc.). The first clue to the biology of the genes underlying these two animal models came from a series of parabiosis experiments conducted by Coleman in the late 1960s [4,5]. Linking the circulation of ob/ob mice with either wild-type or db/db mice promoted weight loss in the ob/ob animals, while parabiosis of db/db mice with either ob/ob or wild-type animals had no effect on the db/db animals-suggesting that ob/ob mice lacked a circulating factor, while db/db mice lacked the receptor for this factor. This conclusion was confirmed by the positional cloning of the ob gene, which encoded an adipocyte (fat cell)-produced secreted peptide (termed leptin; Greek-leptos=thin) that promoted weight loss in ob/ob mice [6]. The leptin receptor (LR)-encoding gene (Lepr) was cloned soon thereafter, revealing that LR mutation underlies the defects in db/db mice [7-10].The physiologic regulation of leptin Although leptin is produced primarily by adipocytes, it is also produced in smaller quantities by other tissues [6,11]. While no conditional null animals have been generated to probe the physiologic relevance of leptin production by specific tissues, the phenotype of human patients and rodent models virtually devoid of adipose tissue (lipodystrophy) is re- Rev Endocr Metab Disord (2007) 8:85-94

Maternal Perinatal Undernutrition Drastically Reduces Postnatal Leptin Surge and Affects the Development of Arcuate Nucleus Proopiomelanocortin Neurons in Neonatal Male Rat Pups

“…As already observed in the rat offspring from prenatally undernourished mothers, a hypercaloric regimen might be required to unmask the metabolic alterations programmed in these animals (6,15). Interestingly, a growing body of evidence indicates that neonatal leptin could play, in addition to the regulation of energy homeostasis, important roles in the control of various neuroendocrine functions, hematopoiesis, lymphopoiesis, and maturation of small intestine (27,28). In particular, it has been reported earlier that neonatal leptin influences the activity of both gonadotroph and hypothalamo-pituitary-adrenal axes (29,30).…”

On the Use of Variance per Genotype as a Tool to Identify Quantitative Trait Interaction Effects: A Report from the Women's Genome Health Study

“…The first interaction involved the leptin receptor SNP rs12753193 in the prediction of CRP. Leptin is a protein synthesized and secreted by the adipose tissue whose main function is to regulate appetite trough interaction with the leptin receptor in the hypothalamus [16]. As such, leptin levels are directly proportional to BMI and patients deficient in either leptin or leptin receptor are characterized by marked obesity [17].…”

High fat diet‐induced maternal obesity alters fetal hippocampal development

“…When on a high fat, dextrose rich diet, adult male rats and mice have decreased brain‐derived neurotrophic factor (Bdnf) levels in the cortex and hippocampus (Yu et al, 2009), associated with alterations in discrimination reversal (Kanoski et al, 2007) and with reduced hippocampal spatial learning performance (Molteni et al, 2002). Another possible mechanism involved in the dietary regulation of hippocampal development is related to the leptin receptor, which is expressed in hippocampus (Louis and Myers, 2007), and may have an important role in facilitating memory and learning (Oomura et al, 2006). Obesity reduces the expression of leptin receptor in liver and hypothalamus (Liu et al, 2007), while lean mice over‐expressed it in the dentate gyrus of the hippocampus (Lin and Huang, 1997).…”