Role of premature leptin surge in obesity resulting from intrauterine undernutrition

Abstract

Intrauterine undernutrition is closely associated with obesity related to detrimental metabolic sequelae in adulthood. We report a mouse model in which offspring with fetal undernutrition (UN offspring), when fed a high-fat diet (HFD), develop pronounced weight gain and adiposity. In the neonatal period, UN offspring exhibited a premature onset of neonatal leptin surge compared to offspring with intrauterine normal nutrition (NN offspring). Unexpectedly, premature leptin surge generated in NN offspring by exogenous leptin administration led to accelerated weight gain with an HFD. Both UN offspring and neonatally leptin-treated NN offspring exhibited an impaired response to acute peripheral leptin administration on a regular chow diet (RCD) with impaired leptin transport to the brain as well as an increased density of hypothalamic nerve terminals. The present study suggests that the premature leptin surge alters energy regulation by the hypothalamus and contributes to "developmental origins of health and disease."

Early and Long-term Undernutrition in Female Rats Exacerbates the Metabolic Risk Associated with Nutritional Rehabilitation

“…Leptin is essential for the connections between NPY neurons and the paraventral nucleus, as well as for POMC projections toward other nuclei (34). Yura et al (27) have reported these disorders in prenatally undernourished mice, which experienced premature leptin surge; these animals developed an obesity-prone phenotype. Offspring of obese rats displayed a prolonged leptin surge and subsequently exhibited hyperphagia (35).…”

“…This does not rule out that other mechanisms, such as bloodbrain barrier disorders, could account for this hyperphagia. Indeed, Yura et al (27) reported impaired transport of leptin across the brain-blood barrier in adult mice with fetal undernutrition. We also found a sharp increase in SOCS3, a suppressor of cytokine signaling, in undernourished rats.…”

Thrifty energy metabolism in catch-up growth trajectories to insulin and leptin resistance

“…16 Of particular relevance to nutritional programming of energy balance are the findings that alterations in maternal and neonatal nutrition can alter the profile of the postnatal leptin surge and hypothalamic development. 17 Indeed, intrauterine under-nutrition in mice resulted in offspring which exhibited a premature leptin surge, and subsequently showed an increased susceptibility to obesity when weaned on a high-fat diet. Thus it appears that the timing of the postnatal leptin surge plays a critical role in the development of hypothalamic circuits that influence food intake and energy expenditure, and that this process can be greatly affected by early nutrition.…”

Developmental programming of the metabolic syndrome - critical windows for intervention

“…Although altered maternal nutrition has been shown to alter the timing and duration of the leptin surge, the results are inconsistent across experimental models. Yura et al [154] reported a premature onset of the neonatal leptin surge following mild (70% of ad-lib) maternal undernutrition whereas MLP offspring display a delayed leptin surge [155] . Work by Delahaye et al [156] showed that maternal perinatal undernutrition drastically reduced the postnatal leptin surge and altered the development of the POMC neurons in the arucate nucleus of neonatal male offspring.…”