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Introduction The epidemics of obesity and type 2 diabetes mellitus (T2DM) pose enormous threats to human health. Weight loss of at least 5%-10% attenuates the severity of these disorders and [...]

Recent genome-wide association studies (GWAS) identified DUSP8, encoding a dual-specificity phosphatase targeting mitogen-activated protein kinases, as a type 2 diabetes (T2D) risk gene. Here, we reveal that Dusp8 is a gatekeeper in the hypothalamic control of glucose homeostasis in mice and humans. Male, but not female, Dusp8 loss-of-function mice, either with global or corticotropin-releasing hormone neuron-specific deletion, had impaired systemic glucose tolerance and insulin sensitivity when exposed to high-fat diet (HFD). Mechanistically, we found impaired hypothalamic- pituitary-adrenal axis feedback, blunted sympathetic responsiveness, and chronically elevated corticosterone levels driven by hypothalamic hyperactivation of Jnk signaling. Accordingly, global Jnk1 ablation, AAV-mediated Dusp8 overexpression in the mediobasal hypothalamus, or metyrapone-induced chemical adrenalectomy rescued the impaired glucose homeostasis of obese male Dusp8-KO mice, respectively. The sex-specific role of murine Dusp8 in governing hypothalamic Jnk signaling, insulin sensitivity, and systemic glucose tolerance was consistent with functional MRI data in human volunteers that revealed an association of the DUSP8 rs2334499 risk variant with hypothalamic insulin resistance in men. Further, expression of DUSP8 was increased in the infundibular nucleus of T2D humans. In summary, our findings suggest the GWAS-identified gene Dusp8 as a novel hypothalamic factor that plays a functional role in the etiology of T2D., Introduction Obesity-induced insulin resistance is associated with an increase in circulating levels of cytokines and free fatty acids (1) that activate proinflammatory signaling pathways. Mitogen-activated protein kinase (MAPK) signaling plays [...]

The metabolic syndrome (MetS) encompasses medical conditions such as obesity, hyperglycemia, high blood pressure, and dyslipidemia that are major drivers for the ever-increasing prevalence of type 2 diabetes, cardiovascular diseases, and certain types of cancer. At the core of clinical strategies against the MetS is weight loss, induced by bariatric surgery, lifestyle changes based on calorie reduction and exercise, or pharmacology. This Review summarizes the past, current, and future efforts of targeting the MetS by pharmacological agents. Major emphasis is given to drugs that target the CNS as a key denominator for obesity and its comorbid sequelae., Introduction The metabolic syndrome (MetS) encompasses a cluster of pernicious metabolic diseases that include visceral obesity, dyslipidemia, hyperglycemia, and hypertension (1). It is considered to be a silent killer owing [...]

We report the discovery of a new monomeric peptide that reduces body weight and diabetic complications in rodent models of obesity by acting as an agonist at three key metabolically-related peptide hormone receptors: glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon receptors. This triple agonist demonstrates supraphysiological potency and equally aligned constituent activities at each receptor, all without cross-reactivity at other related receptors. Such balanced unimolecular triple agonism proved superior to any existing dual coagonists and best-in-class monoagonists to reduce body weight, enhance glycemic control and reverse hepatic steatosis in relevant rodent models. Various loss-of-function models, including genetic knockout, pharmacological blockade and selective chemical knockout, confirmed contributions of each constituent activity in vivo. We demonstrate that these individual constituent activities harmonize to govern the overall metabolic efficacy, which predominantly results from synergistic glucagon action to increase energy expenditure, GLP-1 action to reduce caloric intake and improve glucose control, and GIP action to potentiate the incretin effect and buffer against the diabetogenic effect of inherent glucagon activity. These preclinical studies suggest that, so far, this unimolecular, polypharmaceutical strategy has potential to be the most effective pharmacological approach to reversing obesity and related metabolic disorders., Obesity and its comorbidities, including type 2 diabetes, represent a global health threat and a rapidly increasing burden to economic prosperity (1). Therapeutic intervention is urgently required because lifestyle modification [...]

Although a prominent role for the brain in glucose homeostasis was proposed by scientists in the nineteenth century, research throughout most of the twentieth century focused on evidence that the function of pancreatic islets is both necessary and sufficient to explain glucose homeostasis, and that diabetes results from defects of insulin secretion, action or both. However, insulin-independent mechanisms, referred to as 'glucose effectiveness', account for roughly 50% of overall glucose disposal, and reduced glucose effectiveness also contributes importantly to diabetes pathogenesis. Although mechanisms underlying glucose effectiveness are poorly understood, growing evidence suggests that the brain can dynamically regulate this process in ways that improve or even normalize glycaemia in rodent models of diabetes. Here we present evidence of a brain-centred glucoregulatory system (BCGS) that can lower blood glucose levels via both insulin-dependent and -independent mechanisms, and propose a model in which complex and highly coordinated interactions between the BCGS and pancreatic islets promote normal glucose homeostasis. Because activation of either regulatory system can compensate for failure of the other, defects in both may be required for diabetes to develop. Consequently, therapies that target the BCGS in addition to conventional approaches based on enhancing insulin effects may have the potential to induce diabetes remission, whereas targeting just one typically does not., The escalating epidemic of obesity, metabolic syndrome and type 2 diabetes (T2D) represents one of the most pressing and costly biomedical challenges confronting modern society (1,2). However, much about the [...]

The scaffold protein p62 (sequestosome 1; SQSTM1) is an emerging key molecular link among the metabolic, immune, and proliferative processes of the cell. Here, we report that adipocyte-specific, but not [...]

We report the development of a new combinatorial approach that allows for peptide-mediated selective tissue targeting of nuclear hormone pharmacology while eliminating adverse effects in other tissues. Specifically, we report the development of a glucagon-like peptide-1 (GLP-1)-estrogen conjugate that has superior sex-independent efficacy over either of the individual hormones alone to correct obesity, hyperglycemia and dyslipidemia in mice. The therapeutic benefits are driven by pleiotropic dual hormone action to improve energy, glucose and lipid metabolism, as shown by loss-of-function models and genetic action profiling. Notably, the peptide-based targeting strategy also prevents hallmark side effects of estrogen in male and female mice, such as reproductive endocrine toxicity and oncogenicity. Collectively, selective activation of estrogen receptors in GLP-1--targeted tissues produces unprecedented efficacy to enhance the metabolic benefits of GLP-1 agonism. This example of targeting the metabolic syndrome represents the discovery of a new class of therapeutics that enables synergistic co-agonism through peptide-based selective delivery of small molecules. Although our observations with the GLP-1--estrogen conjugate justify translational studies for diabetes and obesity, the multitude of other possible combinations of peptides and small molecules may offer equal promise for other diseases., Pharmaceutical intervention in chronic diseases often requires a polypharmaceutical approach in which multiple agents individually address specific disease mechanisms. For instance, type 2 diabetes therapy often includes separate drugs targeting [...]

Rodent models of obesity induced by consuming high-fat diet (HFD) are characterized by inflammation both in peripheral tissues and in hypothalamic areas critical for energy homeostasis. Here we report that unlike inflammation in peripheral tissues, which develops as a consequence of obesity, hypothalamic inflammatory signaling was evident in both rats and mice within 1 to 3 days of HFD onset, prior to substantial weight gain. Furthermore, both reactive gliosis and markers suggestive of neuron injury were evident in the hypothalamic arcuate nucleus of rats and mice within the first week of HFD feeding. Although these responses temporarily subsided, suggesting that neuroprotective mechanisms may initially limit the damage, with continued HFD feeding, inflammation and gliosis returned permanently to the mediobasal hypothalamus. Consistent with these data in rodents, we found evidence of increased gliosis in the mediobasal hypothalamus of obese humans, as assessed by MRI. These findings collectively suggest that, in both humans and rodent models, obesity is associated with neuronal injury in a brain area crucial for body weight control., Introduction Obesity has emerged as a major health problem in industrialized nations. Despite substantial progress in understanding the neurobiology of energy homeostasis (the biological process through which energy intake and [...]

Ghrelin is a gastric peptide hormone that stimulates weight gain in vertebrates. The biological activities of ghrelin require octanoylation of the peptide on [Ser.sup.3], an unusual posttranslational modification that is catalyzed by the enzyme ghrelin O-acyltransferase (GOAT). Here, we describe the design, synthesis, and characterization of GO-CoA-Tat, a peptide-based bisubstrate analog that antagonizes GOAT. GO-CoA-Tat potently inhibits GOAT in vitro, in cultured ceils, and in mice. Intraperitoneal administration of GO-CoA-Tat improves glucose tolerance and reduces weight gain in wild-type mice but not in ghrelin-deficient mice, supporting the concept that its beneficial metabolic effects are due specifically to GOAT inhibition. In addition to serving as a research tool for mapping ghrelin actions, GO-CoA-Tat may help pave the way for clinical targeting of GOAT in metabolic diseases. 10.1126/science.1196154

The neuronal circuits involved in the regulation of feeding behavior and energy expenditure are soft-wired, reflecting the relative activity of the postsynaptic neuronal system, including the anorexigenic proopiomelanocortin (POMC)-expressing cells of the arcuate nucleus. We analyzed the synaptic input organization of the melanocortin system in lean rats that were vulnerable (DIO) or resistant (DR) to diet-induced obesity. We found a distinct difference in the quantitative and qualitative synaptology of POMC cells between DIO and DR animals, with a significantly greater number of inhibitory inputs in the POMC neurons in DIO rats compared with DR rats. When exposed to a high-fat diet (HFD), the POMC cells of DIO animals lost synapses, whereas those of DR rats recruited connections. In both DIO rats and mice, the HFD-triggered loss of synapses on POMC neurons was associated with increased glial ensheathment of the POMC perikarya. The altered synaptic organization of HFD-fed animals promoted increased POMC tone and a decrease in the stimulatory connections onto the neighboring neuropeptide Y (NPY) cells. Exposure to HFD was associated with reactive gliosis, and this affected the structure of the blood-brain barrier such that the POMC and NPY cell bodies and dendrites became less accessible to blood vessels. Taken together, these data suggest that consumption of an HFD has a major impact on the cytoarchitecture of the arcuate nucleus in vulnerable subjects, with changes that might be irreversible due to reactive gliosis. synaptic plasticity | brain | inflammation | vulnerability | high-fat diet doi/ 10.1073/pnas.1004282107

Exendin-4 (Ex-4), an agonist of the glucagon-like peptide-1 receptor (GLP-1R), shares many of the actions of GLP-1 on pancreatic islets, the central nervous system (CNS), and the gastrointestinal tract that mediates glucose homeostasis and food intake. Because Ex-4 has a much longer plasma half-life than GLP-1, it is an effective drug for reducing blood glucose levels in patients with type 2 diabetes mellitus (T2DM). Here, we report that acute administration of Ex-4, in relatively high doses, into either the peripheral circulation or the CNS, paradoxically increased blood glucose levels in rats. This effect was independent of the insulinotropic and hypothalamic-pituitary-adrenal activating actions of Ex-4 and could be blocked by a GLP-1R antagonist. Comparable doses of GLP-1 did not induce hyperglycemia, even when protected from rapid metabolism by a dipeptidyl peptidase IV inhibitor. Acute hyperglycemia induced by Ex-4 was blocked by hexamethonium, guanethidine, and adrenal medullectomy, indicating that this effect was mediated by sympathetic nervous system (SNS) activation. The potency of Ex-4 to elevate blood glucose waned with chronic administration such that after 6 days the familiar actions of Ex-4 to improve glucose tolerance were evident. These findings indicate that, in rats, high doses of Ex-4 activate a SNS response that can overcome the expected benefits of this peptide on glucose metabolism and actually raise blood glucose. These results have important implications for the design and interpretation of studies using Ex-4 in rats. Moreover, since there are many similarities in the response of the GLP-1R system across mammalian species, it is important to consider whether there is acute activation of the SNS by Ex-4 in humans. glucagon-like peptide-1; glycemia doi: 10.1152/ajpendo.00464.2009.

Effective control of body weight and energy homeostasis requires stringent regulation of caloric intake and energy expenditure. Gut-brain interactions comprise a central axis for the control of energy homeostasis by integrating the intake of nutrients with an effective utilization of ingested calories either by storage or by expenditure as cellular fuel. Ghrelin, a stomach-derived peptide, is the only known circulating orexigenic hormone. It is acylated with a medium-chain fatty acid by the enzyme ghrelin O-acetyltransferase (GOAT) and displays a broad range of activity, from central control of food intake to peripheral functions such as gastric emptying and insulin secretion. PYY, a peptide produced by L cells of the small intestine and rectum, has been shown to inhibit gut motility and is proposed to stimulate a powerful central satiety response. In recent years, pharmacological studies in animals and clinical studies in humans have contributed to our knowledge of principal ghrelin and PYY actions. However, valuable findings from studies using ghrelin-deficient mice, ghrelin receptor [growth hormone secretagogue receptor-la (GHSR1a)]-deficient mice, double-knockout mice (for ghrelin and GHSR), and GOAT-deficient or -overexpressor mice, as well as mice deficient for PYY or neuropeptide Y receptors have allowed better definition of the actual physiological functions of ghrelin and PYY. This review summarizes findings from mutant mouse studies with emphasis on respective gene knockout and transgenic animals and describes how these studies contribute to the current understanding of how endogenous ghrelin and PYY as two major representatives of endocrine gut-brain communications may regulate energy and glucose homeostasis. peptide YY; neuropeptide Y; ghrelin O-acetyltransferase doi:10.1152/ajpendo.00191.2009.

The orexigenic hormone ghrelin is secreted from the stomach and has been implicated in the regulation of energy and glucose homeostasis. We hypothesized that ghrelin, like other gastrointestinal (GI) hormones, is present in intestinal lymph, and sampling this compartment would provide advantages for studying ghrelin secretion in rodents. Blood and lymph were sampled from catheters in the jugular vein and mesenteric lymph duct before and after intraduodenal (ID) administration of isocaloric Ensure, dextrin, or Liposyn meals or an equal volume of saline in conscious Sprague-Dawley rats. Total ghrelin levels were measured using an established radioimmunoassay. Acyl and des-acyl ghrelin were measured using two-site ELISA. Fasting ghrelin levels in lymph were significantly higher than in plasma (means [+ or -] SE: 3,307.9 [+ or -] 272.9 vs. 2,127.1 [+ or -] 115.0 pg/ml, P = 0.004). Postingestive acyl and des-acyl ghrelin levels were also significantly higher, whereas the ratio of acyl:des-acyl ghrelin was similar in lymph and plasma (0.91 [+ or -] 0.28 vs. 1.20 [+ or -] 0.36, P = 0.76). The principle enzymes responsible for deacylation of ghrelin were lower in lymph than in plasma. Following ID Ensure, maximum ghrelin suppression occurred at 2 h in lymph compared with at 1 h in plasma. The return of suppressed ghrelin levels to baseline was also delayed in lymph. Similarly, dextrin also induced significant suppression of ghrelin (two-way ANOVA: P = 0.02), whereas Liposyn did not (P = 0.32). On the basis of these findings, it appears that intestinal lymph, which includes drainage from the interstitium of the GI mucosa, is enriched in ghrelin. Despite reduced deacylating activity in lymph, there is not a disproportionate amount of acyl ghrelin in this pool. The postprandial dynamics of ghrelin are slower in lymph than plasma, but the magnitude of change is greater. Assessing ghrelin levels in the lymph may be advantageous for studying its secretion and concentrations in the gastric mucosa. metabolism; rats doi:10.1152/ajpgi.00367.2009.

Central nervous system nutrient sensing and afferent endocrine signaling have been established as parallel systems communicating metabolic status and energy availability in vertebrates. The only afferent endocrine signal known to require modification with a fatty acid side chain is the orexigenic hormone ghrelin. We find that the ghrelin O-acyl transferase (GOAT), which is essential for ghrelin acylation, is regulated by nutrient availability, depends on specific dietary lipids as acylation substrates and links ingested lipids to energy expenditure and body fat mass. These data implicate the ghrelin-GOAT system as a signaling pathway that alerts the central nervous system to the presence of dietary calories, rather than to their absence as is commonly accepted., Two discoveries have softened the traditional differentiation between the classic model of nutrient sensing (1) and the concept of endocrine signals controlling energy status (2) by drawing attention to the [...]

Coronary heart disease is a major cause of morbidity and mortality in Western societies. The metabolic syndrome, characterized by obesity, insulin resistance, elevated blood pressure, elevated triglycerides, and low levels of high-density lipoprotein cholesterol, confers substantial risk of coronary heart disease. Current pathogenetic models suggest that postprandial hyper-lipidemia is one specific metabolic abnormality that is typically associated with increased morbidity. In this issue of the JCI, Stanhope and colleagues demonstrate that consumption of fructose-sweetened but not glucose-sweetened beverages for 10 weeks increases de novo lipid synthesis, promotes dyslipidemia, impairs insulin sensitivity, and increases visceral adiposity in overweight or obese adults (see the related article beginning on page 1322)., There is widespread agreement that a chronic, dietary-induced increase of adiposity in humans, beyond a BMI of 30 kg/[m.sup.2], is an unhealthy condition. In the event that any readers harbor [...]

The gut-derived hormone ghrelin exerts its effect on the brain by regulating neuronal activity. Ghrelin-induced feeding behaviour is controlled by arcuate nucleus neurons that co-express neuropeptide Y and agouti-related protein [...]

Menopause and premature gonadal steroid deficiency are associated with increases in fat mass and body weight. Ovariectomized (OVX) mice also show reduced locomotor activity. Glucose-dependent-insulinotropic-polypeptide (GIP) is known to play an important role both in fat metabolism and locomotor activity. Therefore, we hypothesized that the effects of estrogen on the regulation of body weight, fat mass, and spontaneous physical activity could be mediated in part by GIP signaling. To test this hypothesis, C57BL/6 mice and GIP-receptor knockout mice (Gipr.sup.-/-) were exposed to OVX or sham operation (n = 10 per group). The effects on body composition, markers of insulin resistance, energy expenditure, locomotor activity, and expression of hypothalamic anorexigenic and orexigenic factors were investigated over 26 wk in all four groups of mice. OVX wild-type mice developed obesity, increased fat mass, and elevated markers of insulin resistance as expected. This was completely prevented in OVX (Gipr.sup.-/-) animals, even though their energy expenditure and spontaneous locomotor activity levels did not significantly differ from those of OVX wild-type mice. Cumulative food intake in OVX (Gipr.sup.-/-) animals was significantly reduced and associated with significantly lower hypothalamic mRNA expression of the orexigenic neuropeptide Y (NPY) but not of cocaine-amphetamine-related transcript (CART), melanocortin receptors (MCR-3 and MCR-4), or thyrotropin-releasing hormone (TRH). GIP receptors thus interact with estrogens in the hypothalamic regulation of food intake in mice, and their blockade may carry promising potential for the prevention of obesity in gonadal steroid deficiency. estrogen; energy expenditure; body fat

The identification of new pharmacological approaches to effectively prevent, treat, and cure the metabolic syndrome is of crucial importance. Excessive exposure to dietary lipids causes inflammatory responses, deranges the homeostasis of cellular metabolism, and is believed to constitute a key initiator of the metabolic syndrome. Mammalian Sirt1 is a protein deacetylase that has been involved in resveratrol-mediated protection from high-fat diet-induced metabolic damage, but direct proof for the implication of Sirt1 has remained elusive. Here, we report that mice with moderate overexpression of Sirt1 under the control of its natural promoter exhibit fat mass gain similar to wild-type controls when exposed to a high-fat diet. Higher energy expenditure appears to be compensated by a parallel increase in food intake. Interestingly, transgenic Sirt1 mice under a high-fat diet show lower lipid-induced inflammation along with better glucose tolerance, and are almost entirely protected from hepatic steatosis. We present data indicating that such beneficial effects of Sirt1 are due to at least two mechanisms: induction of antioxidant proteins MnSOD and Nrf1, possibly via stimulation of PGC1[alpha], and lower activation of proinflammatory cytokines, such as TNF[alpha] and IL-6, via down-modulation of NF[kappa]B activity. Together, these results provide direct proof of the protective potential of Sirt1 against the metabolic consequences of chronic exposure to a high-fat diet. inflammation | metabolism | NF[kappa]B | sirtuins | steatosis

Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), is the only circulating agent to powerfully promote a positive energy balance. Such action is mediated predominantly by central nervous system pathways controlling food intake, energy expenditure, and nutrient partitioning. The ghrelin pathway may therefore offer therapeutic potential for the treatment of catabolic states. However, the potency of the endogenous hormone ghrelin is limited due to a short half-life and the fragility of its bioactivity ensuring acylation at serine 3. Therefore, we tested the metabolic effects of two recently generated GHS-R agonists, BIM-28125 and BIM-28131, compared with ghrelin. All agents were administered continuously for 1 mo in doses of 50 and 500 nmol * [kg.sup.-1] * [day.sup.1] using implanted subcutaneous minipumps in rats. High-dose treatment with single agonists or ghrelin increased body weight gain by promoting fat mass, whereas BIM-28131 was the only one also increasing lean mass significantly. Food intake increased during treatment with BIM-28131 or ghrelin, whereas no effects on energy expenditure were detected. With the lower dose, only BIM-28131 had a significant effect on body weight. This also held true when the compound was administered by subcutaneous injection three times/day. No symptoms or signs of undesired effects were observed in any of the studies or treated groups. These results characterize BIM-28131 as a promising GHS-R agonist with an attractive action profile for the treatment of catabolic disease states such as cachexia. body weight; food intake; cachexia

Ghrelin is a gut peptide that stimulates food intake and increases body fat mass when administered centrally or peripherally. In this study, ghrelin was overexpressed in neurons using the neuron-specific enolase (NSE) promoter sequences and mouse ghrelin cDNA (NSE-Ghr). Ghrelin expression in NSE-Ghr brain tissues was increased compared with wild-type mice. Ghrelin expression was also increased to a much smaller extent in liver of these mice, but mRNA levels in stomach or duodenum did not differ from wild-type mice. Body weight and composition was analyzed in two lines of NSE-Ghr mice, one line with increased circulating bioactive ghrelin (L43) and one line without (L73). No increases in body weight, food intake, or fat mass were found. Energy expenditure was measured in L43 mice and did not differ from wild-type controls, whereas locomotor activity was increased in NSE-Ghr mice. Young NSE-Ghr mice had normal glucose tolerance; however, L43 NSE-Ghr mice, but not L73 mice, developed glucose intolerance at 32 wk of age. Despite the impaired glucose tolerance in L43 mice, insulin levels did not differ from those of wild-type mice. These findings suggest a role for ghrelin in age-associated impairments of glucose homeostasis. food intake; adipose; obesity

Administration of chemically synthesized ghrelin (Ghr) peptide has been shown to increase food intake and body adiposity in most species. However, the biological role of endogenous Ghr in the molecular control of energy metabolism is far less understood. Mice deficient for either Ghr or its receptor (the growth hormone secretagogue receptor, GHS-R1a) seem to exhibit enhanced protection against high-fat diet-induced obesity but do not show a substantial metabolic phenotype on a standard diet. Here we present the first mouse mutant lacking both Ghr and the Ghr receptor. We demonstrate that simultaneous genetic disruption of both genes of the Ghr system leads to an enhanced energy metabolism phenotype. Ghr/Ghr receptor double knockout (dKO) mice exhibit decreased body weight, increased energy expenditure, and increased motor activity on a standard diet without exposure to a high caloric environment. Mice on the same genetic background lacking either the Ghr or the Ghr receptor gene did not exhibit such a phenotype on standard chow, thereby confirming earlier reports. No differences in food intake, meal pattern, or lean mass were observed between dKO, Ghr-deficient, Ghr receptor-deficient, and wild-type (WT) control mice. Only dKO showed a slight decrease in body length. In summary, simultaneous deletion of Ghr and its receptor enhances the metabolic phenotype of single gene-deficient mice compared with WT mice, possibly suggesting the existence of additional, as of yet unknown, molecular components of the endogenous Ghr system. growth hormone secretagogue receptor, constitutive receptor activity; locomotion

Disruptions of the melanocortin signaling system have been linked to obesity. We investigated a possible role of the central nervous melanocortin system (CNS-Mcr) in the control of adiposity through effects [...]

Diet-induced obesity and its serious consequences such as diabetes, cardiovascular disease, and cancer are rapidly becoming a major global health threat. Therefore, understanding the cellular and molecular mechanisms by which [...]

Obesity is associated with a state of chronic, low-grade inflammation characterized by abnormal cytokine production and macrophage infiltration into adipose tissue, which may contribute to the development of insulin resistance. [...]

The gut hormone ghrelin targets the brain to promote food intake and adiposity. The ghrelin receptor growth hormone secretagogue 1 receptor (GHSR) is present in hypothalamic centers controlling energy metabolism [...]

Many homeostatic processes, including appetite and food intake, are controlled by neuroendocrine circuits involving the CNS. The CNS also directly regulates adipocyte metabolism, as we have shown here by examining [...]

Oleoylethanolamide (OEA), a lipid synthesized in the intestine, reduces food intake and stimulates lipolysis through peroxisome proliferator-activated receptor-[alpha]. OEA also activates transient receptor potential vanilloid type 1 (TRPV1) in vitro. Because the anorexigenic effect of OEA is associated with delayed feeding onset and reduced locomotion, we examined whether intraperitoneal administration of OEA results in nonspecific behavioral effects that contribute to the anorexia in rats. Moreover, we determined whether circulating levels of other gut hormones are modulated by OEA and whether CCK is involved in OEA-induced anorexia. Our results indicate that OEA reduces food intake without causing a conditioned taste aversion or reducing sodium appetite. It also failed to induce a conditioned place aversion. However, OEA induced changes in posture and reduced spontaneous activity in the open field. This likely underlies the reduced heat expenditure and sodium consumption observed after OEA injection, which disappeared within 1 h. The effects of OEA on motor activity were similar to those of the TRPV1 agonist capsaicin and were also observed with the peroxisome proliferator-activated receptor-[alpha] agonist Wy-14643. Plasma levels of ghrelin, peptide YY, glucagon-like peptide 1, and apolipoprotein A-IV were not changed by OEA. Finally, antagonism of CCK-1 receptors did not affect OEA-induced anorexia. These results suggest that OEA suppresses feeding without causing visceral illness and that neither ghrelin, peptide YY, glucagon-like peptide 1, apolipoprotein A-IV, nor CCK plays a critical role in this effect. Despite that OEA-induced anorexia is unlikely to be due to impaired motor activity, our data raise a cautionary note in how specific behavioral and metabolic effects of OEA should be interpreted. peroxisome proliferator-activated receptor-[alpha]; transient receptor potential vanilloid type 1; cholecystokinin; satiety; obesity

Obesity represents one of the most urgent global health threats as well as one of the leading causes of death throughout industrialized nations. Efficacious and safe therapies remain at large. Attempts to decrease fat mass via pharmacological reduction of energy intake have had limited potency or intolerable side effects. Increasingly widespread sedentary lifestyle is often cited as a major contributor to the increasing prevalence of obesity. Moreover, low levels of spontaneous physical activity (SPA) are a major predictor of fat mass accumulation during overfeeding in humans, pointing to a substantial role for SPA in the control of energy balance. Despite this, very little is known about the molecular mechanisms by which SPA is regulated. The overview will attempt to summarize available information on neuroendocrine factors regulating SPA. KEY WORDS: * ghrelin * physical activity * energy expenditure * AGRP * NPY * CART * leptin

Employing in vitro selection techniques, we have generated biostable RNA-based compounds, so-called Spiegelmers, that specifically hind n-octanoyl ghrelin, the recently discovered endogenous ligand for the type 1a growth hormone secretagogue (GHS) receptor. Ghrelin is a potent stimulant of growth hormone release, food intake, and adiposity. We demonstrate that our lead compound, L-NOX-B11, binds ghrelin with low-nanomolar affinity and inhibits ghrelin-mediated GHS-receptor activation in cell culture with an [IC.50] of 5 nM. L-NOX-B11 is highly specific for the bioactive, n-octanoylated form of ghrelin. Like the GHS receptor, it does not recognize the inactive unmodified peptide and requires only the N-terminal five amino acids for the interaction. The i.v. administration of polyethylene glycol modified L-NOX-B11 efficiently suppresses ghrelin-induced growth hormone release in rats. These results demonstrate that the neutralization of circulating bioactive ghrelin leads to inhibition of ghrelin's secretory effects in the CNS.

Who among us hasn't fantasized about a diet that allows ingestion of a surfeit of calories that are burned off effortlessly by ramping up energy expenditure? In this issue of the JCI, research led by Christopher Morrison suggests that this dream may become a reality; however, a complete understanding of the molecular interface that connects nutrient choices with our cellular metabolism will be required. Laeger et al. show that the expression and secretion of the weight-reducing hormone fibroblast growth factor 21 (FGF21) is regulated by dietary proteins and not, as has been heretofore assumed, simply triggered by reduced caloric intake. This study not only sheds new light on the role of FGF21 in systems metabolism, but also on the ways our bodies cope with the ever-changing availability of different dietary macronutrients., FGF21 production benefits energy metabolism After an exhausting day and when craving dinner, not many of us appreciate that over the course of the day, various signaling molecules have been [...]

Prouroguanylin is a gastrointestinal paracrine signal and prohormone that is secreted after nutrient ingestion. In this issue of the JCI, Valentino et al. show that prouroguanylin is converted to uroguanylin in the CNS, which can activate guanylyl cyclase 2C (GUCY2C) receptors in the brain to reduce food intake in mice. This 16-amino acid residue peptide is a novel component of the gut-brain axis that represents a new and unique opportunity to manipulate gut-brain signaling for therapeutic intervention in obesity., Life as an endocrinologist is getting complicated these days. A few decades ago, there were just a small number of endocrine organs, including the thyroid, adrenals, and pancreas. Over the [...]

Nature 454, 846-851 (2008) In Fig. 3a and b of this Article, the pAMPK samples were spliced. Images of the uninterrupted AMPK together with the uninterrupted pAMPK samples are now [...]

Rethinking Thin: The New Science of Weight Loss--and the Myths and Realities of Dieting Gina Kolata Farrar, Straus and Giroux, 2007 272 pp., hardcover, $24.00 ISBN: 0374103984 The conclusions to [...]