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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 [...]

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

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 [...]

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.