Physiological signals critical periods and hypothalamic mechanisms underlying neonatal programming of adult hyperphagia by maternal over-nutrition

广泛的流行病学和动物研究表明，母亲肥胖不仅加剧了通常与怀孕有关的并发症，而且增加了后代患代谢和心血管疾病的长期风险。这种影响不依赖于任何直接的遗传原因。母亲获得的特征的遗传引起了重要的生物学问题;因此，这种现象的全部意义超出了能量平衡的直接背景。尽管如此，这些发现的直接影响为肥胖问题的不断升级提供了重要的视角，肥胖问题威胁着我们的医疗服务。我们最近开发了一种实验方案，在该方案中，雌性大鼠或小鼠在受孕前以及整个妊娠期和哺乳期都被给予富含糖和脂肪的非常可口的饮食。这种饮食导致明显的肥胖，并模仿了整个西半球普遍食用的致肥食物。虽然这些啮齿动物的幼崽从断奶开始就以正常的饮食喂养，但到成年时，它们表现出食欲增加和肥胖，并有2型糖尿病和心血管疾病的迹象。15年前，人们发现了一种由脂肪细胞分泌的新激素，并将其命名为瘦素（leptin，来自希腊语leptos，意思是瘦）。当在成年期给予正常啮齿动物或缺乏这种激素的小鼠时，瘦素会抑制进食。然而，在慢性肥胖病例中，瘦素是无效的;在这种情况下，人类和啮齿动物被认为是瘦素抵抗的。在出生后的前十天，啮齿动物在血液中产生大量的瘦素。这进入大脑，促进下丘脑（大脑中控制食欲的部分）通路的生长。我们在啮齿动物中发现的一个最显著的变化是，由于母体营养过剩而导致的食欲旺盛，在断奶前瘦素的大量增加和延长。我们还发现，这些动物在出生后30天（断奶后9天），早在他们明显肥胖之前，就出现了瘦素抵抗。这些动物表现出瘦素抑制进食行为的能力的丧失，以及通常由瘦素在下丘脑的食欲调节部分内诱导的细胞活性的减少。这些发现使我们假设母乳中的化学信号促进了幼崽血液中瘦素的异常激增。我们还假设，随后过度刺激下丘脑中的瘦素敏感回路导致慢性瘦素抵抗和持续不受限制的食欲。这项拟议中的研究将阐明从母亲那里收到的化学信号，以及这些信号通过过量分泌瘦素影响婴儿未来食欲的关键时期。增加产妇饮食中有益脂肪酸的比例的治疗可能性将得到解决。我们也将阐明导致下丘脑成为瘦素抵抗的过程和对食欲调节回路的影响。这些研究将增加我们对母体肥胖可能影响后代长期健康的生物学机制的理解。

Extensive epidemiological and animal-based studies have demonstrated that maternal obesity not only heightens the complications commonly associated with pregnancy, but also increases the long-term risks of metabolic and cardiovascular disease in offspring. This effect is independent of any direct genetic cause. Inheritance of a characteristic which has been acquired by the mother raises important biological issues; consequently, the full significance of this phenomenon extends beyond the immediate context of energy balance. Nevertheless, the immediate implications of these findings provide important perspectives on the escalating problems of obesity, which threaten to overwhelm our healthcare services. We have recently developed an experimental protocol in which female rats or mice are given a highly palatable diet, rich in sugar and fat, before conception and throughout gestation and lactation. This diet results in overt obesity and mimics the obesogenic food which is commonly eaten throughout the western hemisphere. Although the pups of these rodents are raised on a normal diet from weaning, by adulthood they show increased appetite and obesity, with signs of type-2 diabetes and cardiovascular disease. Fifteen years ago a novel hormone secreted by fat cells was discovered and named leptin (from the Greek leptos, meaning thin). When administered in adulthood to normal rodents or to mice which are deficient of this hormone, leptin suppresses feeding. In chronic cases of obesity, however, leptin is ineffective; under such conditions, humans and rodents are said to be leptin-resistant. During the first ten days after birth, rodents produce a surge of leptin in the blood. This enters the brain and promotes the growth of pathways in the hypothalamus, the part of the brain which controls appetite. One of the most striking changes we have found in the rodents programmed for high appetite by maternal over-nutrition is a massively raised and prolonged surge of leptin before weaning. We have also found leptin-resistance in these animals by postnatal day 30 (9 days after weaning), long before they are overtly obese. These animals show a loss of leptin's ability to suppress feeding behaviour, and also a reduction in the cellular activity normally induced by leptin within the appetite-regulating part of the hypothalamus. These findings lead us to hypothesise that chemical signals in the mother's milk promote the abnormal surge of leptin in the pup's blood. We also hypothesise that the consequent over-stimulation of leptin-sensitive circuits in the hypothalamus results in chronic leptin-resistance and a persistently unrestrained appetite. The proposed research will elucidate the chemical signals received from the mother and the critical period during which those signals influence the infant's future appetite by excess secretion of leptin. The therapeutic possibilities of increasing the ratio of beneficial fatty acids in the maternal diet will be addressed. We will also elucidate the processes causing the hypothalamus to become leptin-resistant and the effects on appetite-regulating circuits. These studies will increase our understanding of the biological mechanisms which underlie the ways in which maternal obesity may influence the long-term health of offspring.