Exposure to a High-Fat Diet During Development Alters Leptin and Ghrelin Sensitivity and Elevates Renal Sympathetic Nerve Activity and Arterial Pressure in Rabbits

Abstract

With the rising prevalence of obesity, particularly among women of reproductive age, it is important to understand the consequences of maternal obesity and nutrient excess on processes underlying development because they may lead to adverse outcomes in offspring. Animal models of maternal fat-rich diets that reflect the dietary intakes of humans in affluent societies have demonstrated the programming of offspring hyperphagia, adiposity, insulin resistance, and hypertension.1,2 Various factors, including elevated blood pressure (BP), insulin resistance, hyperglycemia, elevated plasma glucocorticoids, and leptin, associated with obesity during gestation can affect the development of a fetus.3 These factors can all contribute to a suboptimal intrauterine environment and predispose offspring to an increased risk of obesity and hypertension. There is evidence that the sympathetic nervous system (SNS) may be activated in offspring of fat-fed dams that develop hypertension, 1 but to date no study has shown direct evidence for increased sympathetic vasomotor activity. The adipokine hormone leptin and the gut hormone ghrelin act on neural circuitry of the hypothalamus important for energy homeostasis and the regulation of the SNS. 4,5 We have recently shown that the renal sympathetic nerve activity (RSNA) and BP increases in the first few days of consuming a high-fat diet (HFD) in rabbits can be largely reversed by a leptin antagonist given intracerebroventricularly (ICV). [6][7][8][9] In contrast, ghrelin secreted by the stomach activates arcuate neurons containing neuropeptide Y and agouti-related protein and has been shown to suppress sympathetic activity, decrease BP, and stimulate appetite.10,11 Thus, both leptin and ghrelin may play a key role in the association between obesity and hypertension and may also be involved in the hypertension programmed by a maternal HFD (m-HFD).The purpose of this study was to examine the effect of an m-HFD during development on arterial pressure and RSNA and the central sympathetic effects of leptin and ghrelin in offspring. We used a rabbit model in which an HFD induces elevated BP and RSNA. [6][7][8][9] We hypothesized that offspring exposed to an HFD during development would retain greater deposits of fat and show a selective leptin-resistant phenotype Abstract-Exposure to maternal obesity or a maternal diet rich in fat during development may have adverse outcomes in offspring, such as the development of obesity and hypertension. The present study examined the effect of a maternal high-fat diet (m-HFD) on offspring blood pressure and renal sympathetic nerve activity, responses to stress, and sensitivity to central administration of leptin and ghrelin. Offspring of New Zealand white rabbits fed a 13% HFD were slightly heavier than offspring from mothers fed a 4% maternal normal fat diet (P<0.05) but had 64% greater fat pad mass (P=0.015). Mean arterial pressure, heart rate, and renal sympathetic nerve activity at 4 months of age were 7%, 7%, and 24% greater, respectively (P<0.001),...

Developmental programming by maternal obesity in 2015: Outcomes, mechanisms, and potential interventions

“…Studies in rabbits and rats have suggested that changes in sympathetic tone may be an important mediator of these effects. Maternal HFD in rabbits increases renal sympathetic nerve activity in the offspring (Prior et al, 2014). Likewise studies suggest that maternal obesity in rats induces hypertension in the offspring via increased sympathetic drive in early development (Samuelsson et al, 2010), which may be mediated by altered early life leptin signalling.…”

Leptin stimulates sympathetic axon outgrowth

“…Abnormal leptin expression can alter β3-adreneric receptor expression in cardiac myocytes [44] and induce ventricular hypertrophy resulting in higher mortality in mice [45]. Recent studies have shown that animals fed a high fat diet have an increased risk of ventricular arrhythmias and sudden cardiac death [21,46, 47]. Sympathetic hyperinnervation in the heart has been linked to arrhythmias in animals and humans [48, 49].…”

Effect of Maternal Obesity on Foetal Growth and Metabolic Health of the Offspring

“…The mechanisms linking maternal malnutrition and excessive weight in pregnancy to later-life metabolic health of the offspring are unclear. Some evidence is available on the association between maternal diet and reduced leptin or insulin sensitivity as well as reduction of sympathetic activity within the adipose tissue of the offspring [21,22,23]. Leptin, insulin, glucocorticoids and ghrelin are involved in metabolic programming mechanisms at both central (CNS) and peripheral levels (adipose tissue, liver, skeletal muscle) [21,22,24].…”