Peptide-YY3-36/glucagon-like peptide-1 combination treatment of obese diabetic mice improves insulin sensitivity associated with recovered pancreatic ß-cell function and synergistic activation of discrete hypothalamic and brainstem neuronal circuitries.

OBJECTIVE: Obesity-linked type 2 diabetes (T2D) is a worldwide health concern and many novel approaches are being considered for its treatment and subsequent prevention of serious comorbidities. Co-administration of glucagon like peptide 1 (GLP-1) and peptide YY3-36 (PYY3-36) renders a synergistic decrease in energy intake in obese men. However, mechanistic details of the synergy between these peptide agonists and their effects on metabolic homeostasis remain relatively scarce. METHODS: In this study, we utilized long-acting analogues of GLP-1 and PYY3-36 (via Fc-peptide conjugation) to better characterize the synergistic pharmacological benefits of their co-administration on body weight and glycaemic regulation in obese and diabetic mouse models. Hyperinsulinemic-euglycemic clamps were used to measure weight-independent effects of Fc-PYY3-36 + Fc-GLP-1 on insulin action. Fluorescent light sheet microscopy analysis of whole brain was performed to assess activation of brain regions. RESULTS: Co-administration of long-acting Fc-IgG/peptide conjugates of Fc-GLP-1 and Fc-PYY3-36 (specific for PYY receptor-2 (Y2R)) resulted in profound weight loss, restored glucose homeostasis, and recovered endogenous ß-cell function in two mouse models of obese T2D. Hyperinsulinemic-euglycemic clamps in C57BLKS/J db/db and diet-induced obese Y2R-deficient (Y2RKO) mice indicated Y2R is required for a weight-independent improvement in peripheral insulin sensitivity and enhanced hepatic glycogenesis. Brain cFos staining demonstrated distinct temporal activation of regions of the hypothalamus and hindbrain following Fc-PYY3-36 + Fc-GLP-1R agonist administration. CONCLUSIONS: These results reveal a therapeutic approach for obesity/T2D that improved insulin sensitivity and restored endogenous ß-cell function. These data also highlight the potential association between the gut-brain axis in control of metabolic homeostasis.

Ninjin'yoeito modulates feeding and activity under negative energy balance conditions via the NPY system.

The central and peripheral neuropeptide Y (NPY) system is critically involved in feeding and energy homeostasis control. Disease conditions as well as aging can lead to reduced functionality of the NPY system and boosting it represents a promising option to improve health outcomes in these situations. Here we show that Ninjin-yoeito (NYT), a Japanese kampo medicine comprising twelve herbs, and known to be effective to treat anorexia and frailty, mediates part of its action via NPY/peptide YY (PYY) related pathways. Especially under negative energy homeostasis conditions NYT is able to promote feeding and reduces activity to conserve energy. These effects are in part mediated via signalling through the NPY system since lack of Y4 receptors or PYY leading to modification in these responses highlighting the possibility for combination treatment to improve aging related conditions on energy homeostasis control.

Effects of fasting and re-feeding on the expression of CCK, PYY, hypothalamic neuropeptides, and IGF-related genes in layer and broiler chicks.

Cholecystokinin (CCK) and peptide YY (PYY) have been investigated as gut hormones that send satiation signals to the brain in mammals. There is evidence that chicken PYY mRNA expression was the highest in the pancreas compared to other tissues. We recently suggested that insulin-like growth factor (IGF)-1 and its binding proteins (IGFBPs) may be involved in the appetite regulation system in chicks. In the present study, in order to evaluate the possible roles of CCK, PYY, and IGF-related proteins in the appetite regulation system in chicks, we analyzed changes in the mRNA levels of these genes in response to fasting and re-feeding in layer and hyperphagic broiler chicks. In layer chicks, 12 h of fasting reduced the mRNA levels of intestinal CCK, PYY, Y2 receptor, and pancreatic PYY, and these changes were reversed by 12 h of re-feeding. On the other hand, in broiler chicks 12 h of fasting reduced the mRNA levels of intestinal PYY and Y2 receptor, but not intestinal CCK and pancreatic PYY, and these changes were reversed by 12 h of re-feeding. Hypothalamic NPY mRNA significantly increased by 12 h of fasting in both chicks, and these changes were reversed by re-feeding. Also, 12 h of fasting significantly increased the mRNA levels of hypothalamic agouti-related protein and reduced the mRNA levels of hepatic IGF-1 only in broiler chicks, and 12 h of re-feeding did not change these. IGFBP-1 and -2 mRNA levels were markedly increased by 12 h of fasting in both chicks, and these changes were reversed by re-feeding. IGFBP-3 mRNA levels were increased by 12 h of fasting only in layer chicks, while re-feeding reduced the mRNA levels of IGFBP-3 in both types of chicks. These results suggest that several peripheral hormones, such as pancreatic PYY and intestinal CCK, may not play important roles in the regulation of food intake in broiler chicks.

Neuronal Control of Bone Remodeling.

Although the brain is well established as a master regulator of homeostasis in peripheral tissues, central regulation of bone mass represents a novel and rapidly expanding field of study. This review examines the current understanding of central regulation of the skeleton, exploring several of the key pathways connecting brain to bone and their implications both in mice and the clinical setting. Our understanding of central bone regulation has largely progressed through examination of skeletal responses downstream of nutrient regulatory pathways in the hypothalamus. Mutations and modulation of these pathways, in cases such as leptin deficiency, induce marked bone phenotypes, which have provided vital insights into central bone regulation. These studies have identified several central neuropeptide pathways that stimulate well-defined changes in bone cell activity in response to changes in energy homeostasis. In addition, this work has highlighted the endocrine nature of the skeleton, revealing a complex cross talk that directly regulates other organ systems. Our laboratory has studied bone-active neuropeptide pathways and defined osteoblast-based actions that recapitulate central pathways linking bone, fat, and glucose homeostasis. Studies of neural control of bone have produced paradigm-shifting changes in our understanding of the skeleton and its relationship with the wider array of organ systems.

Gut and hormones and obesity.

Following the discovery of secretin in 1902, a host of further peptide hormones that are synthesised and released from the gastrointestinal tract have been identified. While their roles in the regulation of gastrointestinal function have been known for some time, it is now evident that many of these hormones also physiologically regulate energy balance. Our understanding of how gut hormones signal to the brain has advanced significantly in recent years. Several hormones, including peptide YY, pancreatic polypeptide, oxyntomodulin, glucagon-like peptide 1 and cholecystokinin function as satiety signals. In contrast, only ghrelin, produced by the stomach, has emerged as a putative hunger signal, appearing to act both as a meal initiator and a long-term body weight regulator. Recent research suggests that gut hormones can be manipulated to regulate energy balance in man and that obese subjects retain sensitivity to the actions of gut hormones. The worldwide obesity pandemic continues unabated, despite public health initiatives and current best therapy. Future gut hormone-based therapies may provide an effective and well-tolerated treatment for obesity.

Pathophysiology of obesity: why surgery remains the most effective treatment.

Obesity is a rapidly increasing, worldwide epidemic. Despite recent scientific advances, no currently recommended dietary program or medication results in long-term weight loss of more than 10% of body weight for the vast majority of people who attempt these interventions. Hence, surgical intervention is recommended for patients with a BMI > or =40 kg/m2. Although surgery is an effective, sustainable treatment of obesity, it can be associated with potentially significant perioperative risks and long-term complications. Current research is focused on developing a medical therapy, which produces more effective and sustainable weight loss, yet avoids the risks inherent in major surgery. With a reduced risk profile, such therapy could also be appropriately offered to those who are less obese and, in theory, help those who have BMIs as low as 27 kg/m2. Toward that end, numerous scientists are working to both unravel the pathophysiology of obesity and to determine why surgical intervention is so effective. This review briefly examines the current status of obesity pathophysiology and management, the reasons for failure of conventional medical treatments, and the success of surgical intervention. Finally, future areas of research are discussed.

Appetite regulation: an overview.

Obesity is a major public health problem associated with morbidity and mortality and continues to increase worldwide. This review focuses on the regions of the brain that are important in appetite regulation and the circulating factors implicated in the control of food intake. The hypothalamus is critical in the regulation of food intake containing neural circuits, which produce a number of peptides that influence food intake. The arcuate nucleus of the hypothalamus produces both orexigenic peptides (agouti-related protein and neuropeptide Y) and anorectic peptides (alpha-melanocyte-stimulating hormone and cocaine- and amphetamine-related transcript). The lateral hypothalamus produces the orexigenic peptides (melanin-concentrating hormone and orexins). Other hypothalamic factors recently implicated in appetite regulation include the endocannabinoids, brain-derived neurotrophic factor, nesfatin-1, AMP-activated protein kinase, mammalian target of rapamycin protein, and protein tyrosine phosphatase. Circulating factors that affect food intake mediate their effects by signaling to the hypothalamus and/or brainstem. A number of circulating factors are produced by peripheral organs, for example, leptin by adipose tissue, insulin and pancreatic polypeptide by the pancreas, gut hormones (e.g., ghrelin, obestatin, glucagon-like peptide-1, oxyntomodulin, peptide YY), and triiodothyronine by the thyroid gland. Circulating carbohydrates, lipids, and amino acids also affect appetite regulation. Knowledge regarding appetite regulation has vastly expanded in recent years providing targets for antiobesity drug design.

[Ghrelin, a new hormone involved not only in the regulation of appetite]. / Ghrelina, nowy hormon uczestniczacy nie tylko w regulacji apetytu.

Recent progress in the field of energy homeostasis was triggered by the discovery of adipocyte hormone leptin and revealed a complex regulatory neuroendocrine network, which precisely regulates appetite. Discovery of ghrelin, a novel hormone derived from the stomach, has illustrated the relationship of the stomach and hypothalamus which is a crucial missing link in the regulation of energy balance, growth and coordinated gastrointestinal function. The discovery of ghrelin opens new perspectives of research with potential therapeutic relevance in patients with gastrointestinal, metabolic, endocrine and other diseases.

Ingested fat and satiety.

Apolipoprotein A-IV (apo A-IV) is secreted by the intestine associated with chylomicron. Intestinal apo A-IV synthesis is stimulated by fat absorption, probably mediated by chylomicron formation. The stimulation of apo A-IV synthesis in the jejunum and ileum is attenuated by intravenous leptin infusion. Intestinal apo A-IV synthesis is also stimulated by a factor from the ileum, probably peptide tyrosine-tyrosine (PYY), which has been demonstrated to affect satiety. Apo A-IV has been proposed to physiologically control food intake, and this inhibitory effect is centrally mediated. Recently, apo A-IV was demonstrated in the hypothalamus. The hypothalamic apo A-IV level was reduced by food deprivation and restored by lipid feeding. Intracerebroventricular administration of apo A-IV antiserum stimulated feeding and decreased the hypothalamic apo A-IV mRNA level, implying that feeding is normally limited by endogenous apo A-IV. Central administration of neuropeptide Y (NPY) significantly increased hypothalamic apo A-IV mRNA levels in a dose-dependent manner. The stimulation of intestinal synthesis and secretion of apo A-IV by lipid absorption are rapid; thus, apo A-IV is capable of short-term regulation of food intake. Evidence also suggests apo A-IV's involvement in long-term regulation of food intake and bodyweight. The chronic ingestion of high fat blunts the intestinal apo A-IV response to lipid feeding and may therefore explain why chronic intake of high fat predisposes animals and humans to obesity.