Abstract
BackgroundEpidemiological data have shown long-term health adversity in low birth weight subjects, especially concerning the metabolic syndrome and ‘diabesity’ risk. Alterations in adult food intake have been suggested to be causally involved. Responsible mechanisms remain unclear.Methods and FindingsBy rearing in normal (NL) vs. small litters (SL), small-for-gestational-age (SGA) rats were neonatally exposed to either normal (SGA-in-NL) or over-feeding (SGA-in-SL), and followed up into late adult age as compared to normally reared appropriate-for-gestational-age control rats (AGA-in-NL). SGA-in-SL rats displayed rapid neonatal weight gain within one week after birth, while SGA-in-NL growth caught up only at juvenile age (day 60), as compared to AGA-in-NL controls. In adulthood, an increase in lipids, leptin, insulin, insulin/glucose-ratio (all p<0.05), and hyperphagia under normal chow as well as high-energy/high-fat diet, modelling modern ‘westernized’ lifestyle, were observed only in SGA-in-SL as compared to both SGA-in-NL and AGA-in-NL rats (p<0.05). Lasercapture microdissection (LMD)-based neuropeptide expression analyses in single neuron pools of the arcuate hypothalamic nucleus (ARC) revealed a significant shift towards down-regulation of the anorexigenic melanocortinergic system (proopiomelanocortin, Pomc) in SGA-in-SL rats (p<0.05). Neuropeptide expression within the orexigenic system (neuropeptide Y (Npy), agouti-related-peptide (Agrp) and galanin (Gal)) was not significantly altered. In essence, the ‘orexigenic index’, proposed here as a neuroendocrine ‘net-indicator’, was increased in SGA-in-SL regarding Npy/Pomc expression (p<0.01), correlated to food intake (p<0.05).ConclusionAdult SGA rats developed increased ‘diabesity’ risk only if exposed to neonatal overfeeding. Hypothalamic malprogramming towards decreased anorexigenic activity was involved into the pathophysiology of this neonatally acquired adverse phenotype. Neonatal overfeeding appears to be a critical long-term risk factor in ‘small-for-gestational-age babies’.
Highlights
Prevalence of obesity, diabetes and accompanying disturbances has increased globally reaching epidemic levels in adults, adolescents and even children [1,2,3,4]
Hypothalamic malprogramming towards decreased anorexigenic activity was involved into the pathophysiology of this neonatally acquired adverse phenotype
SGA rats exposed to neonatal overnutrition by rearing in small litters (SGA-in-SL) showed rapid neonatal weight gain
Summary
Prevalence of obesity, diabetes and accompanying disturbances has increased globally reaching epidemic levels in adults, adolescents and even children [1,2,3,4]. Since the early 1990s, great attention has been given to the association between a low birth weight (LBW) and long-term risk of developing cardiovascular diseases, type 2 diabetes and the metabolic syndrome. A ‘thrifty phenotype’ acquired in utero through poor fetal nutrition should enable affected individuals to better adaptation towards reduced food availability in later life [5,7]. When those individuals are exposed to affluent conditions later on, according to the hypothesis this acquired disposition leads to the development of type 2 diabetes, cardiovascular diseases, and the metabolic syndrome.
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