Ghrelin, a stomach-derived orexigenic hormone, has stimulated great interest as a potential target for obesity control. Pharmacological evidence indicates that ghrelin’s effects on food intake are ...mediated by neuropeptide Y (NPY) and agouti-related protein (AgRP) in the central nervous system. These include intracerebroventricular application of antibodies to neutralize NPY and AgRP, and the application of an NPY Y1 receptor antagonist, which blocks some of the orexigenic effects of ghrelin. Here we describe treatment of Agrp−/−;Npy−/− and Mc3r−/−;Mc4r−/− double knockout mice as well as Npy−/− and Agrp−/− single knockout mice with either ghrelin or an orally active nonpeptide ghrelin agonist. The data demonstrate that NPY and AgRP are required for the orexigenic effects of ghrelin, as well as the involvement of the melanocortin pathway in ghrelin signaling. Our results outline a functional interaction between the NPY and AgRP pathways. Although deletion of either NPY or AgRP caused only a modest or nondetectable effect, ablation of both ligands completely abolished the orexigenic action of ghrelin. Our results establish an in vivo orexigenic function for NPY and AgRP, mediating the effect of ghrelin.
We use single photon detectors to probe the motional state of a superfluid ^{4}He resonator of mass ∼1 ng. The arrival times of Stokes and anti-Stokes photons (scattered by the resonator's acoustic ...mode) are used to measure the resonator's phonon coherences up to the fourth order. By postselecting on photon detection events, we also measure coherences in the resonator when ≤3 phonons have been added or subtracted. These measurements are found to be consistent with predictions that assume the acoustic mode to be in thermal equilibrium with a bath through a Markovian coupling.
Melanin-concentrating hormone (MCH) is a cyclic 19-aa hypothalamic neuropeptide derived from a larger prohormone precursor of MCH (Pmch), which also encodes neuropeptide EI (NEI) and neuropeptide GE ...(NGE). Pmch-deficient (Pmch-/-) mice are lean, hypophagic, and have an increased metabolic rate. Transgenic mice overexpressing Pmch are hyperphagic and develop mild obesity. Consequently, MCH has been implicated in the regulation of energy homeostasis. The MCH 1 receptor (MCH1R) is one of two recently identified G protein-coupled receptors believed to be responsible for the actions of MCH. We evaluated the physiological role of MCH1R by generating MCH1R-deficient (Mch1r-/-) mice. Mch1r-/-mice have normal body weights, yet are lean and have reduced fat mass. Surprisingly, Mch1r-/-mice are hyperphagic when maintained on regular chow, and their leanness is a consequence of hyperactivity and altered metabolism. Consistent with the hyperactivity, Mch1r-/-mice are less susceptible to diet-induced obesity. Importantly, chronic central infusions of MCH induce hyperphagia and mild obesity in wild-type mice, but not in Mch1r-/-mice. We conclude that MCH1R is a physiologically relevant MCH receptor in mice that plays a role in energy homeostasis through multiple actions on locomotor activity, metabolism, appetite, and neuroendocrine function.
Genetic and pharmacological
studies have defined a role for the melanocortin-4 receptor (Mc4r) in the
regulation of energy homeostasis. The physiological function of Mc3r, a melanocortin
receptor ...expressed at high levels in the hypothalamus, has
remained unknown. We evaluated the potential role of Mc3r in energy homeostasis
by studying Mc3r-deficient (Mc3r−/−) mice
and compared the functions of Mc3r and Mc4r in mice deficient
for both genes. The 4-6-month Mc3r−/−
mice have increased fat mass, reduced lean mass and higher feed efficiency
than wild-type littermates, despite being hypophagic and maintaining normal
metabolic rates. (Feed efficiency is the ratio of weight gain to food intake.)
Consistent with increased fat mass, Mc3r−/−
mice are hyperleptinaemic and male Mc3r−/−
mice develop mild hyperinsulinaemia. Mc3r−/−
mice did not have significantly altered corticosterone or total thyroxine
(T4) levels. Mice lacking both Mc3r and Mc4r become significantly
heavier than Mc4r−/− mice. We conclude that
Mc3r and Mc4r serve non-redundant roles in the regulation of energy homeostasis.
Abstract Chronic social disruption stress (SDR) exacerbates acute and chronic phase Theiler's murine encephalomyelitis virus (TMEV) infection, a mouse model of multiple sclerosis. However, the ...precise mechanism by which this occurs remains unknown. The present study suggests that SDR exacerbates TMEV disease course by priming virus-induced neuroinflammation. It was demonstrated that IL-1β mRNA expression increases following acute SDR; however, IL-6 mRNA expression, but not IL-1β, is upregulated in response to chronic SDR. Furthermore, this study demonstrated SDR prior to infection increases infection related central IL-6 and IL-1β mRNA expression, and administration of IL-6 neutralizing antibody during SDR reverses this increase in neuroinflammation.
We evaluated the role of the melanocortin-4 receptor (MC-4R) in the control of metabolic rate and food intake in mice. Intraperitoneal administration of the non-selective MC-R agonist melanotan II ...(MT-II; a cyclic heptapeptide) increases metabolic rate in wildtype mice, while MC-4R knockout mice are insensitive to the effects of MT-II on metabolic rate. MC-4R knockout mice are also insensitive to the effects of MT-II on reducing food intake. We conclude that MC-4R can mediate control of both metabolic rate and food intake in mice. We infer that a role for MC-3R in mediating the acute effects of MT-II on basal metabolic rate and food intake in wildtype mice seems limited.
This study prospectively examined the relationships among late night salivary cortisol (NSC) levels and depressive symptoms, memory performance, and hippocampal volumes in patients with medically ...intractable temporal lobe epilepsy (TLE) and the potential mediating effects of cortisol in the relationships between these variables.
Participants included 24 adults with well-characterized medically refractory TLE (right = 11; left = 12; bitemporal = 1). All patients provided saliva samples and completed measures of mood, anxiety, and memory (objective and subjective). MRI-based volumetric analyses of the hippocampi were also conducted.
As hypothesized, cortisol was found to be negatively related to several memory measures such that patients with higher cortisol levels demonstrated lower memory performance. However, unexpectedly, cortisol was not related to current symptoms of depression or anxiety, subjective memory ratings, or hippocampal volumes. Consistent with previous findings in the literature, a number of other relationships among the study variables were observed (objective memory and hippocampal volume; subjective memory and mood/anxiety). Results of mediator analyses suggested that cortisol does not mediate the relationship between depression and memory dysfunction or the relationship between depression and hippocampal atrophy.
While cortisol may play a role in memory performance in patients with TLE, it does not fully explain the relationship between depression and mesial temporal dysfunction, likely reflecting the complex and multifactorial relationships among these variables. Results confirm the relationship between memory performance and structural brain integrity and provide further support for a role of depression in subjective memory complaints.
Tooth eruption is a complex and tightly regulated process that involves cells of the tooth organ and the surrounding alveolus. Mononuclear cells (osteoclast precursors) must be recruited into the ...dental follicle prior to the onset of eruption. These cells, in turn, fuse to form osteoclasts that resorb alveolar bone, forming an eruption pathway for the tooth to exit its bony crypt. Some of the molecules possibly involved in the signaling cascades of eruption have been proposed in studies from null mice, osteopetrotic rodents, injections of putative eruption molecules, and cultured dental follicle cells. In particular, recruitment of the mononuclear cells to the follicle may require colony-stimulating factor-one (CSF-1) and/or monocyte chemotactic protein-1 (MCP-1). Osteoclastogenesis is needed for the bone resorption and may involve inhibition of osteoprotegerin transcription and synthesis in the follicle, as well as enhancement of receptor activator of NF kappa B ligand (RANKL), in the adjacent alveolar bone and/or in the follicle. Paracrine signaling by parathyroid-hormone-related protein and interleukin -1 alpha, produced in the stellate reticulum adjacent to the follicle, may also play a role in regulating eruption. Osteoblasts might also influence the process of eruption, the most important physiologic role likely being at the eruptive site, in the formation of osteoclasts through signaling via the RANKL/OPG pathway. Evidence thus far supports a role for an osteoblast-specific transcription factor, Cbfa1 (Runx2), in molecular events that regulate tooth eruption. Cbfa1 is also expressed at high levels by the dental follicle cells. This review concludes with a discussion of the several human conditions that result in a failure of or delay in tooth eruption.
Xenopus laevis oocytes were injected with mRNA isolated from the free-living nematode Caenorhabditis elegans and the activation and potentiation of a glutamate-sensitive chloride current by a series ...of avermectin analogs and milbemycin D were determined. There was a strong correlation between the EC50value determined for current activation in oocytes, the LD95value for nematocidal activity, and also for the Ki value determined in a 3Hivermectin competition binding assay. Four of the analogs were tested for potentiation of glutamate-sensitive current and the rank order for potentiation correlated with the EC50for direct activation of current. We conclude that avermectins and milbemycins mediate their nematocidal effects on C. elegans via an interaction with a common receptor molecule, glutamate-gated chloride channels.
To determine the mechanism of ventricular vulnerability to electrical stimulation, we simultaneously recorded from 120 transmural electrodes in a 35 X 20 X 5-mm portion of right ventricular ...infundibulum in seven dogs. Baseline pacing (S1) was performed from outside the mapped region followed by single premature stimulation (S2) of increasing strength at the center of the mapped region. In five of six episodes of ventricular fibrillation and 26 of 30 episodes of repetitive responses, complete reentrant pathways were observed. Earliest activation following S2 was not at the site of S2 stimulation but was at a point between the S1 and S2 sites of stimulation. Activation spread away from the early site toward the opposite side of the mapped region around the sides of an arc of block near the S2 site to form a "figure-of-eight." The activation fronts coalesced to activate the region around the S2 site last and, if the difference in times between activation at the early site and near the S2 site was large, reentered the tissue toward the S1 site. Ventricular refractory periods were determined in four dogs following S1 pacing; the regions with the greatest nonuniformity in the dispersion of refractoriness were not the regions of unidirectional block after S2 stimulation. Thus, 1) ventricular fibrillation and repetitive responses induced electrically with S1 and S2 stimuli at different ventricular sites arise by figure-of-eight reentry, 2) this reentry is caused by the ability of S2 stimulation both to prolong refractoriness near the S2 site and to initiate a propagated response in the region between the S1 and S2 sites, and 3) a nonuniform dispersion of refractoriness is not crucial for the electrical induction of reentry leading to ventricular fibrillation or repetitive responses when S1 and S2 stimuli are given at different locations on the right ventricular outflow tract.
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