Abstract
LEP is a pleiotropic gene and the actions of leptin extend well beyond simply acting as the signal of the size of adipose tissue stores originally proposed. This is a discussion of the multi-system interactions of leptin with the development of the neural systems regulating energy stores, and the subsequent maintenance of energy stores throughout the lifespan. The prenatal, perinatal, and later postnatal effects of leptin on systems regulating body energy stores and on the energy stores themselves are heavily influenced by the nutritional environment which leptin exposure occurs. This review discusses the prenatal and perinatal roles of leptin in establishing the neuronal circuitry and other systems relevant to the adiposity set-point (or “threshold”) and the role of leptin in maintaining weight homeostasis in adulthood. Therapeutic manipulation of the intrauterine environment, use of leptin sensitizing agents, and identification of specific cohorts who may be more responsive to leptin or other means of activating the leptin signaling pathway are ripe areas for future research.
Highlights
In 1973, Coleman (1973) demonstrated that parabiosis of the obese mice with diabetes mice and wild type mice resulted in hypophagia and starvation of the Lepob mice while not affecting the phenotype of the Leprdb mice
Leibel and Hirsch (1984) and others (Welle et al, 1984) found that reduced body weight maintenance was accompanied by a decline in energy expenditure and an increase in hunger disproportionate to changes in body weight and composition that strongly resembled the metabolic state of the Lepob and Leprdb mice
The advent of large-scale genome-wide association studies (GWAS) combined with polygenic risk scoring has facilitated the identification of aggregate genetic factors determining body weight and the underlying energy homeostatic mechanisms that regulate it
Summary
In 1973, Coleman (1973) demonstrated that parabiosis of the obese (later Lepob) mice with diabetes (later Leprdb) mice and wild type mice resulted in hypophagia and starvation of the Lepob mice while not affecting the phenotype of the Leprdb mice. HFD feeding during pregnancy in rodents is associated with disruptions in the normal patterns of projections in the hypothalamic feeding circuits, including decreased AgRP immunoreactive fibers in the PVH (Kirk et al, 2009; Vogt et al, 2014) and reduced density of α-MSH projections from the ARH to PVH, DMH and LHA in 8-week old progeny (Vogt et al, 2014) These are the same projections disrupted in congenitally leptin deficient mice suggesting that effects of maternal diet on the weight of the offspring may be mediated through effects on the postnatal leptin surge which, in turn, alters the development of the feeding circuitry
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