α-Melanocyte stimulating hormone promotes muscle glucose uptake via melanocortin 5 receptors.

OBJECTIVE: Central melanocortin pathways are well-established regulators of energy balance. However, scant data exist about the role of systemic melanocortin peptides. We set out to determine if peripheral α-melanocyte stimulating hormone (α-MSH) plays a role in glucose homeostasis and tested the hypothesis that the pituitary is able to sense a physiological increase in circulating glucose and responds by secreting α-MSH. METHODS: We established glucose-stimulated α-MSH secretion using humans, non-human primates, and mouse models. Continuous α-MSH infusions were performed during glucose tolerance tests and hyperinsulinemic-euglycemic clamps to evaluate the systemic effect of α-MSH in glucose regulation. Complementary ex vivo and in vitro techniques were employed to delineate the direct action of α-MSH via the melanocortin 5 receptor (MC5R)-PKA axis in skeletal muscles. Combined treatment of non-selective/selective phosphodiesterase inhibitor and α-MSH was adopted to restore glucose tolerance in obese mice. RESULTS: Here we demonstrate that pituitary secretion of α-MSH is increased by glucose. Peripheral α-MSH increases temperature in skeletal muscles, acts directly on soleus and gastrocnemius muscles to significantly increase glucose uptake, and enhances whole-body glucose clearance via the activation of muscle MC5R and protein kinase A. These actions are absent in obese mice, accompanied by a blunting of α-MSH-induced cAMP levels in skeletal muscles of obese mice. Both selective and non-selective phosphodiesterase inhibition restores α-MSH induced skeletal muscle glucose uptake and improves glucose disposal in obese mice. CONCLUSION: These data describe a novel endocrine circuit that modulates glucose homeostasis by pituitary α-MSH, which increases muscle glucose uptake and thermogenesis through the activation of a MC5R-PKA-pathway, which is disrupted in obesity.

Consumption of a Western-style diet during pregnancy impairs offspring islet vascularization in a Japanese macaque model.

Children exposed to a maternal Western-style diet in utero have an increased risk of developing type 2 diabetes. Understanding the mechanisms and an investigation of possible interventions are critical to reversing this phenomenon. We examined the impact of maternal Western-style diet consumption on the development of islet vascularization and innervation, both of which are critical to normal islet function, in fetal and juvenile offspring. Furthermore, we assessed whether improved dietary intake or resveratrol supplementation could ameliorate the harmful consequences of Western-style diet consumption during pregnancy. Adult female Japanese macaques were maintained on a control or Western-style diet for 4-7 yr. One cohort of dams was switched back onto a control diet, whereas another cohort received resveratrol supplementation throughout gestation. Pregnancies were terminated in the early third trimester by C-section, or offspring were born naturally and sent to necropsy at 1 yr of age. Western-style diet consumption resulted in impaired fetal islet capillary density and sympathetic islet innervation. Furthermore, this reduction in vascularization persisted in the juvenile offspring. This effect is independent of changes in the expression of key angiogenic markers. Diet reversal normalized islet vascularization to control offspring levels, whereas resveratrol supplementation caused a significant increase in capillary density above controls. These data provide a novel mechanism by which maternal Western-style diet consumption leads to increased susceptibility to type 2 diabetes in the offspring. Importantly, an improved maternal diet may mitigate these harmful effects. However, until the long-term consequences of increased vascularization can be determined, resveratrol use during pregnancy is not advised.

High-fat diet consumption during pregnancy and the early post-natal period leads to decreased α cell plasticity in the nonhuman primate.

We investigated the impact of poor maternal nutrition and metabolic health on the development of islets of the nonhuman primate (NHP). Interestingly, fetal offspring of high fat diet (HFD) fed animals had normal total islet and ß cell mass; however, there was a significant reduction in α cell mass, and decreased expression of transcription factors involved in α cell differentiation. In juvenile animals all offspring maintained on a HFD during the postweaning period demonstrated increases in total islet mass, however, the control offspring displaying increased islet number, and HFD offspring displayed increased islet size. Finally, while control offspring had increases in α and ß cells, the HFD offspring had increases only in ß cell number. These studies indicate that consumption of a HFD diet during pregnancy in the NHP, independent of maternal metabolic health, causes long-term abnormalities in α cell plasticity that may contribute to chronic disease susceptibility.

Maternal high fat diet is associated with decreased plasma n-3 fatty acids and fetal hepatic apoptosis in nonhuman primates.

To begin to understand the contributions of maternal obesity and over-nutrition to human development and the early origins of obesity, we utilized a non-human primate model to investigate the effects of maternal high-fat feeding and obesity on breast milk, maternal and fetal plasma fatty acid composition and fetal hepatic development. While the high-fat diet (HFD) contained equivalent levels of n-3 fatty acids (FA's) and higher levels of n-6 FA's than the control diet (CTR), we found significant decreases in docosahexaenoic acid (DHA) and total n-3 FA's in HFD maternal and fetal plasma. Furthermore, the HFD fetal plasma n-6:n-3 ratio was elevated and was significantly correlated to the maternal plasma n-6:n-3 ratio and maternal hyperinsulinemia. Hepatic apoptosis was also increased in the HFD fetal liver. Switching HFD females to a CTR diet during a subsequent pregnancy normalized fetal DHA, n-3 FA's and fetal hepatic apoptosis to CTR levels. Breast milk from HFD dams contained lower levels of eicosopentanoic acid (EPA) and DHA and lower levels of total protein than CTR breast milk. This study links chronic maternal consumption of a HFD with fetal hepatic apoptosis and suggests that a potentially pathological maternal fatty acid milieu is replicated in the developing fetal circulation in the nonhuman primate.