Pre- and postnatal nutrition in sheep affects β-cell secretion and hypothalamic control

Abstract

Maternal undernutrition increases the risk of type 2 diabetes and metabolic syndrome later in life, particularly upon postnatal exposure to a high-energy diet. However, dysfunctions of, for example, the glucose-insulin axis are not readily detectable by conventional tests early in life, making it difficult to identify individuals at risk. Thus, other methods are required. We hypothesised that prenatally undernourished individuals (but not postnatally overnourished ones) are adapted to a life with limited food availability, which would be evident under conditions reflecting starvation, stress and short-term abundance of food. In this study, twinpregnant sheep were fed diets meeting 100% (NORM) or 50% (LOW) of energy and protein requirements during the last trimester. Twin offspring were fed either a normal moderate (CONV) diet or a high-carbohydrate-high-fat (HCHF) diet from 3 days to 6 months of age (approximately puberty) and the same moderate diet thereafter until 2 years of age (young adulthood; only females), resulting in four groups: NORM-CONV, LOW-CONV, NORM-HCHF and LOW-HCHF. At the age of 6 months and 2 years respectively, they were subjected to fasting and propionate (nutrient abundance) and adrenalin challenges. At 6 months of age, postnatal HCHF diet exposure caused metabolic alterations, reflecting hypertriglyceridaemia and altered pancreatic b-cell secretion. Irrespective of postnatal diet, prenatal undernutrition was found to be associated with unexpected endocrine responses of leptin, IGF1 and cortisol during fasting (lack of or the opposite response compared with the controls) in 2-year-old adults. In conclusion, a HCHF diet interfered with b-cell function, whereas maternal undernutrition did not lead to any changes in the LOW offspring, except to abnormal hormone responses, suggesting that fetal programming interferes with hypothalamic integration of important endocrine axis.

Do very small adipocytes in subcutaneous adipose tissue (a proposed risk factor for insulin insensitivity) have a fetal origin?

“…It should be noted that the impacts of prenatal and early-postnatal nutrition on adipose tissues characteristics at 6-months of age can be evaluated for males only, and at 2-years of age only for females, since all males had to be sacrificed at 6-months of age due to practical constraints. However, metabolic and endocrine responses during glucose, insulin and fasting tolerance tests were evaluated as previously reported [16,22] in all female and male lambs at 6-months of age, where gender effects were rare and mainly associated with fat deposition patterns [14]. Age-related changes for the mentioned traits have been evaluated in the female sheep studied at both 6-months and 2-years of age [16,22].…”

“…However, metabolic and endocrine responses during glucose, insulin and fasting tolerance tests were evaluated as previously reported [16,22] in all female and male lambs at 6-months of age, where gender effects were rare and mainly associated with fat deposition patterns [14]. Age-related changes for the mentioned traits have been evaluated in the female sheep studied at both 6-months and 2-years of age [16,22]. These previously published results will be referred to in the discussion when relevant to put the present findings into perspective.…”

Famine Exposure during the Fetal Period Increased the Risk of Dyslipidemia in Female Adults

“…Another possible mechanism involves early life programming of the hypothalamic–pituitary–adrenal (HPA) axis, which links prenatal development to disease later in life (Reynolds, ). Previous studies proved that nutritional deficiency during the prenatal and postnatal stages may lead to perpetual changes in hypothalamic gene expression that are the main causes of endocrine and metabolic diseases (Breton, ; Kongsted et al, ; Orozcosolís et al, ). Increased HPA axis activity in offspring was related to unfavorable uterine conditions and persisted in adulthood (Van et al, ).…”

Pre‐natal undernutrition and post‐natal overnutrition are associated with permanent changes in hepatic metabolism markers and fatty acid composition in sheep

“…, Kongsted et al . , 2014). HCHF lambs became obese with high plasma gamma‐glutamyl‐transferase levels and clear signs of hepatic steatosis.…”

“…The profound hepatic steatosis in HCHF‐fed lambs can be ascribed to high hepatic uptake of bloodborne, dietary‐derived FAs driven by excessive blood levels of non‐esterified fatty acids and TG (Kongsted et al . , 2014). A key marker of hepatic de novo lipogenesis, SREBP1c , was down‐regulated in HCHF lambs, and its down‐stream target, FAS , was unaffected by the post‐natal diet, suggesting that de novo lipogenesis did not contribute to hepatic steatosis.…”