Trypsin and mast cell tryptase cleave proteinase-activated receptor 2 and, by unknown mechanisms, induce widespread inflammation. We found that a large proportion of primary spinal afferent neurons, which express proteinase-activated receptor 2, also contain the proinflammatory neuropeptides calcitonin gene-related peptide and substance P. Trypsin and tryptase directly signal to neurons to stimulate release of these neuropeptides, which mediate inflammatory edema induced by agonists of proteinase-activated receptor 2. This new mechanism of protease-induced neurogenic inflammation may contribute to the proinflammatory effects of mast cells in human disease. Thus, tryptase inhibitors and antagonists of proteinase-activated receptor 2 may be useful anti-inflammatory agents.
Accelerating crop improvement in sorghum, a staple food for people in semiarid regions across the developing world, is key to ensuring global food security in the context of climate change. To facilitate gene discovery and molecular breeding in sorghum, we have characterized ∼265,000 single nucleotide polymorphisms (SNPs) in 971 worldwide accessions that have adapted to diverse agroclimatic conditions. Using this genome-wide SNP map, we have characterized population structure with respect to geographic origin and morphological type and identified patterns of ancient crop diffusion to diverse agroclimatic regions across Africa and Asia. To better understand the genomic patterns of diversification in sorghum, we quantified variation in nucleotide diversity, linkage disequilibrium, and recombination rates across the genome. Analyzing nucleotide diversity in landraces, we find evidence of selective sweeps around starch metabolism genes, whereas in landrace-derived introgression lines, we find introgressions around known height and maturity loci. To identify additional loci underlying variation in major agroclimatic traits, we performed genome-wide association studies (GWAS) on plant height components and inflorescence architecture. GWAS maps several classical loci for plant height, candidate genes for inflorescence architecture. Finally, we trace the independent spread of multiple haplotypes carrying alleles for short stature or long inflorescence branches. This genome-wide map of SNP variation in sorghum provides a basis for crop improvement through marker-assisted breeding and genomic selection.Sorghum bicolor | quantitative trait locus | adaptation
Endocannabinoids and ghrelin are potent appetite stimulators and are known to interact at a hypothalamic level. However, both also have important peripheral actions, including beneficial effects on the ischemic heart and increasing adipose tissue deposition, while ghrelin has direct effects on carbohydrate metabolism. The AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme that functions as a fuel sensor to regulate energy balance at both cellular and whole body levels, and it may mediate the action of anti-diabetic drugs such as metformin and peroxisome proliferator-activated receptor ␥ agonists. Here we show that both cannabinoids and ghrelin stimulate AMPK activity in the hypothalamus and the heart, while inhibiting AMPK in liver and adipose tissue. These novel effects of cannabinoids on AMPK provide a mechanism for a number of their known actions, such as the reduction in infarct size in the myocardium, an increase in adipose tissue, and stimulation of appetite. The beneficial effects of ghrelin on heart function, including reduction of myocyte apoptosis, and its effects on lipogenesis and carbohydrate metabolism, can also be explained by its ability to activate AMPK. Our data demonstrate that AMPK not only links the orexigenic effects of endocannabinoids and ghrelin in the hypothalamus but also their effects on the metabolism of peripheral tissues.Endocannabinoids, acting via the presynaptic cannabinoid type 1 receptor (CB 1 ), 1 stimulate appetite in the hypothalamus(1), but direct peripheral effects have also been observed in animal studies implicating endocannabinoids in peripheral signaling of nutritional status and lipogenesis (2). The CB 1 antagonist rimonabant (SR141716) inhibits food intake, and phase III clinical trials have shown sustained effects on weight loss in humans through effects on glucose and fat metabolism (3-5).Ghrelin is a circulating brain-gut peptide with growth hormone-releasing and appetite-inducing effects, with predominant expression in the gastric mucosa but low level widespread expression throughout the body (6 -8). Intracerebroventricular (i.c.v.) ghrelin treatment increases appetite and body weight, with a direct stimulatory effect on adipose tissue deposition demonstrated in both in vivo and in vitro studies (9, 10). It has been suggested that ghrelin favors preservation of lipid stores and the catabolism of carbohydrate-derived fuel, thereby increasing the respiratory quotient (11, 12). Ghrelin levels are high during fasting and in subjects with low body mass index, while low ghrelin levels are observed after food intake and in patients with insulin-resistant states such as type 2 diabetes, obesity, or polycystic ovarian syndrome (8). Both cannabinoids and ghrelin have been shown to have beneficial effects on the ischemic heart (13, 14). We have previously shown that ghrelin and the endocannabinoid system interact, as subanorectic doses of rimonabant can inhibit the orexigenic effect of ghrelin (15). Here we demonstrate a previously unrecognized interaction betw...
Ghrelin stimulates food intake and adiposity and thereby increases body weight (BW) in rodents after central as well as peripheral administration. Recently, it was discovered that the gene precursor of ghrelin encoded another secreted and bioactive peptide named obestatin. First reports appeared to demonstrate that this peptide requires an amidation for its biological activity and acts through the orphan receptor, GPR-39. Obestatin was shown to have actions opposite to ghrelin on food intake, BW, and gastric emptying. In the present study, we failed to observe any effect of obestatin on food intake, BW, body composition, energy expenditure, locomotor activity, respiratory quotient, or hypothalamic neuropeptides involved in energy balance regulation. In agreement with the first report, we were unable to find any effect of obestatin on GH secretion in vivo. Moreover, we were unable to find mRNA expression of GPR-39, the putative obestatin receptor, in the hypothalamus of rats. Therefore, the results presented here do not support a role of the obestatin/GPR-39 system in the regulation of energy balance.
Faced with reduced levels of food, animals must adjust to the consequences of the shortfall in energy. We explored how C57BL/6 mice withdrew energy from different body tissues during three months of food restriction at graded levels up to 40% (calorie restriction: CR). We compared this to the response to equivalent levels of protein restriction (PR) without a shortfall in calories. Under CR there was a dynamic change in body mass over 30 days and thereafter it stabilized. The time to reach stability was independent of the level of restriction. At the end of three months whole body dissections revealed differential utilization of the different tissues. Adipose tissue depots were the most significantly utilized tissue, and provided 55.8 to 60.9% of the total released energy. In comparison, reductions in the sizes of structural tissues contributed between 29.8 and 38.7% of the energy. The balance was made up by relatively small changes in the vital organs. The components of the alimentary tract grew slightly under restriction, particularly the stomach, and this was associated with a parallel increase in assimilation efficiency of the food (averaging 1.73%). None of the changes under CR were recapitulated by equivalent levels of PR.
Limiting food intake attenuates many of the deleterious effects of aging, impacting upon healthspan and leading to an increased lifespan. Whether it is the overall restriction of calories (calorie restriction: CR) or the incidental reduction in macronutrients such as protein (protein restriction: PR) that mediate these effects is unclear. The impact of 3 month CR or PR, (10 to 40%), on C57BL/6 mice was compared to controls fed ad libitum. Reductions in circulating leptin, tumor necrosis factor-α and insulin-like growth factor-1 (IGF-1) were relative to the level of CR and individually associated with morphological changes but remained unchanged following PR. Glucose tolerance and insulin sensitivity were improved following CR but not affected by PR. There was no indication that CR had an effect on oxidative damage, however CR lowered antioxidant activity. No biomarkers of oxidative stress were altered by PR. CR significantly reduced levels of major urinary proteins suggesting lowered investment in reproduction. Results here support the idea that reduced adipokine levels, improved insulin/IGF-1 signaling and reduced reproductive investment play important roles in the beneficial effects of CR while, in the short-term, attenuation of oxidative damage is not applicable. None of the positive effects were replicated with PR.
The anorexigenic and orexigenic hormones leptin and ghrelin act in opposition to one another. When leptin signaling is reduced, as in the Zucker fatty rat, or when circulating ghrelin is increased during fasting, the effect of ghrelin becomes more dominant, indicating an influence of both hormones on ghrelin action. This effect could be mediated via the level of expression of ghrelin receptor (growth hormone secretagogue receptor [GHS-R]). For testing this, GHS-R expression was measured using in situ hybridization in Zucker fatty versus lean rats; in fed versus fasted (48 h) rats, treated with either ghrelin or leptin; and in GH-deficient, dwarf versus control rats. In the arcuate nuclei of the Zucker fatty rat and in fasted rats, GHS-R expression is significantly increased. A single leptin intracerebroventricular injection attenuated the fasting-induced increase in GHS-R but had no effect in fed rats 2 h after injection, whereas leptin infusion for 24 h or longer significantly decreased GHS-R expression in fed rats. Ghrelin significantly increased GHS-R expression but not in dwarf rats. These results show that the level of GHS-R expression in the ARC is reduced by leptin and increased by ghrelin and that the effect of ghrelin may be GH dependent.
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