Prenatal influences on susceptibility to diet-induced obesity are mediated by altered neuroendocrine gene expression

Abstract

The escalating rates of obesity and type 2 diabetes have reached pandemic proportions. It has been proposed that the risk of developing metabolic disorders in adult life is influenced by environmental factors, which operate during the early periods of development. We have previously shown that an interaction between the prenatal and the postnatal dietary environment amplifies the propensity towards dietinduced obesity, although the mechanisms are unclear. In the present study, we investigated the interaction between prenatal undernutrition and postnatal high-fat nutrition on key genes of the hypothalamic appetite regulatory network. Pregnant Wistar rats were fed a standard chow diet either ad libitum (AD) or at 30% of AD intake throughout gestation (UN). From weaning, female AD and UN offspring were fed either a standard chow (ADC nZ8, UNC nZ8) or a high-fat diet (45% kcal as fat; ADHF nZ8, UNHF nZ8) ad libitum for the remainder of the study. At 24 weeks of age, body composition was assessed by dual energy X-ray absorptiometry analysis and total RNA was extracted from whole rat hypothalami. Real-time PCR was performed to characterise pro-opiomelanocortin (POMC), neuropeptide Y (NPY), agouti-related protein (AgRP) and OBRb gene expression at the mRNA level. Our results demonstrate that the amplification of postnatal obesity develops as a consequence of an interaction between prenatal undernutrition and postnatal high-fat nutrition. This phenotype also shows significant alterations in POMC, NPY, AgRP and OBRb gene expression together with elevations in circulating levels of both plasma leptin and insulin. These findings are consistent with the predictive adaptive response hypothesis that neuroendocrine development during fetal life may be based on predictions about postnatal environmental conditions. Increased susceptibility to diet-induced obesity develops if a mismatch between the anticipated and the actual conditions are encountered.

The hypothalamus–adipose axis is a key target of developmental programming by maternal nutritional manipulation

“…Indeed, post-weaning high-fat (HF) diet exacerbated the catch-up growth of rat offspring from FR70 dams during gestation, leading to higher energy intake and adiposity. Elevated NPY mRNA expression levels were observed in adulthood (Ikenasio-Thorpe et al 2007).…”

Developmental and epigenetic pathways to obesity: an evolutionary-developmental perspective

“…48 The animals have neuroendocrine alterations in the hypothalamus. 49 They are also sarcopenic, develop endothelial dysfunction, visceral, hepatic and subcutaneous obesity and have disordered expression of metabolic genes in peripheral tissues. This suggests that there is a coordinated central and peripheral response to an impaired fetal experience.…”

Developmental programming of the metabolic syndrome - critical windows for intervention

“…These offspring display increased adiposity, hypertension, hyperinsulinemia, hyperleptinemia, reduced locomotor activity, leptin resistance and hyperphagia in adult life [47,72,73] . Severe global undernutrition has also been shown to result in altered neuroendocrine gene expression, including pro-opiomelanocortin (POMC), agoutirelated peptide and neuropeptide Y [74,75] . When the degree of undernutrition is reduced to a more moderate level, i.e.…”