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Diabetes, obesity, and Alzheimer's disease (AD) are associated with vascular complications and impaired nitric oxide (NO) production. Furthermore, increased p-site amyloid precursor protein-cleaving (APP-cleaving) enzyme 1 (BACE1), APP, and [beta]-amyloid (A[beta]) are linked with vascular disease development and increased BACE1 and A[beta] accompany hyperglycemia and hyperlipidemia. However, the causal relationship between obesity and diabetes, increased A[beta], and vascular dysfunction is unclear. We report that diet-induced obesity (DIO) in mice increased plasma and vascular A[beta]42 that correlated with decreased NO bioavailability, endothelial dysfunction, and increased blood pressure. Genetic or pharmacological reduction of BACE1 activity and A[beta]42 prevented and reversed, respectively, these outcomes. In contrast, expression of human mutant APP in mice or A[beta]42 infusion into control diet-fed mice to mimic obese levels impaired NO production, vascular relaxation, and raised blood pressure. In humans, increased plasma A[beta]42 correlated with diabetes and endothelial dysfunction. Mechanistically, higher A[beta]42 reduced endothelial NO synthase (eNOS), cyclic GMP (cGMP), and protein kinase G (PKG) activity independently of diet, whereas endothelin-1 was increased by diet and A[beta]42. Lowering A[beta]42 reversed the DIO deficit in the eNOS/cGMP/PKG pathway and decreased endothelin-1. Our findings suggest that BACE1 inhibitors may have therapeutic value in the treatment of vascular disease associated with diabetes., Introduction There is increasing evidence that links vascular disease and endothelial dysfunction (as found in obesity, diabetes, and hypercholesterolemia; i.e., metabolic syndrome) with Alzheimer's disease (AD) and cognitive impairment, through [...]

High-fat diets are known to decrease muscle protein synthesis, the adaptation to overload, and insulin sensitivity. Conditions that disrupt endoplasmic reticulum (ER) homeostasis lead to the activation of the unfolded protein response (UPR) that is associated with decreases in protein synthesis, chronic inflammation, and insulin resistance. The purpose of the present study was to establish whether ER stress is induced by a high-fat diet in skeletal muscle and whether ER stress can decrease mTORC1 activity and protein synthesis in muscle cells. Two independent protocols of high-fat feeding activated the UPR in mice. In the first study, mice consuming a high-fat diet containing 70% fat and < 1% carbohydrates for 6 wk showed higher markers of the UPR (BiP, IRE1[alpha], and MBTPS2) in the soleus and in the tibialis anterior muscles and ATF4 in the tibialis anterior (P < 0.05). In the second study, a 20-wk high-fat diet containing 46% fat and 36% carbohydrates also increased BiP, IRE1[alpha], and phospho-PERK protein and the expression of ATF4, CHOP, and both the spliced and unspliced forms of XBP1 in the plantar flexors (P < 0.05). In [C.sub.2][C.sub.12] muscle cells, tunicamycin, thapsigargin, and palmitic acid all increased UPR markers and decreased phosphorylation of S6K1 (P < 0.05). Collectively, these data show that a high-fat diet activates the UPR in mouse skeletal muscle in vivo. In addition, in vitro studies indicate that palmitic acid, and other well-known ER stress inducers, triggered the UPR in myogenic cells and led to a decrease in protein synthesis and mTORC1 activity. endoplasmic reticulum stress; binding protein; X box binding protein-1; ribosomal protein S6 kinase; protein synthesis doi: 10.1152/ajpendo.00038.2010.

Hypothalamic AMP-activated protein kinase (AMPK) has been suggested to act as a key sensing mechanism, responding to hormones and nutrients in the regulation of energy homeostasis. However, the precise neuronal [...]

Calcium ion dependent and calcium independent potassium channels in human myometrium exhibited differences in sensitivity relative to specific and nonspecific potassium channel blockers. It was further revealed that based on cell-attached recordings for inside-out patches of nonlabor and labor freshly dispersed human pregnant myometrial cells, the properties of large-conductance potassium channels in myocytes isolated from laboring patients are also significantly different from those isolated from nonlaboring patients.

Abstract: A number of hormones, including leptin, have been shown to inhibit food intake in humans and animals. Analogues of 3-guanidinopropionic acid have also been found to reduce total food intake, but their mechanisms of action have not been well studied. The present study investigated the effects of intracerebroventricular infusion of the analogue BVT.3531 on food intake, meal pattern, and body weight in rats during 7 days. Single channel recordings from arcuate neurons and insulinoma cells were used to determine the effects of BVT.3531 on KATP activity. Data analysis showed that BVT.3531 significantly decreased body weight and food intake, primarily by reducing meal size. BVT.3531 activated KATP channels in cell-attached recordings from insulin-secreting cells and rat arcuate neurons but had no effect on KATP channel activity in inside-out membrane patches from either cell type. BVT.3531 did not alter the firing rate or K+ channel activity of arcuate neurons devoid of KATP. The study suggests that small molecules capable of mimicking the effects of leptin on food intake and body weight may utilize output mechanisms similar to those of leptin to elicit changes in arcuate neuron excitability. [Copyright &y& Elsevier]

Insulin receptor substrate 2 (Irs2) plays complex roles in energy homeostasis. We generated mice lacking Irs2 in beta cells and a population of hypothalamic neurons (RIPCreIrs2KO), in all neurons (NesCreIrs2KO), and in proopiomelanocortin neurons (POMCCreIrs2KO) to determine the role of Irs2 in the CNS and beta cell. RIPCreIrs2KO mice displayed impaired glucose tolerance and reduced beta cell mass. Overt diabetes did not ensue, because beta cells escaping Cre-mediated recombination progressively populated islets. RIPCreIrs2KO and NesCreIrs2KO mice displayed hyperphagia, obesity, and increased body length, which suggests altered melanocortin action. POMCCreIrs2KO mice did not display this phenotype. RIPCreIrs2KO and NesCreIrs2KO mice retained leptin sensitivity, which suggests that CNS Irs2 pathways are not required for leptin action. NesCreIrs2KO and POMCCreIrs2KO mice did not display reduced beta cell mass, but NesCreIrs2KO mice displayed mild abnormalities of glucose homeostasis. RIPCre neurons did not express POMC or neuropeptide Y. Insulin and a melanocortin agonist depolarized RIPCre neurons, whereas leptin was ineffective. Insulin hyperpolarized and leptin depolarized POMC neurons. Our findings demonstrate a critical role for IRS2 in beta cell and hypothalamic function and provide insights into the role of RIPCre neurons, a distinct hypothalamic neuronal population, in growth and energy homeostasis. [ABSTRACT FROM AUTHOR]