calcitonin and Anorexia

The behavioral mechanisms and the neuronal pathways mediated by amylin and its long-acting analog sCT (salmon calcitonin) are not fully understood and it is unclear to what extent sCT and amylin engage overlapping or distinct neuronal subpopulations to reduce food intake. We here hypothesize that amylin and sCT recruit different neuronal population to mediate their anorectic effects.. Viral approaches were used to inhibit calcitonin gene-related peptide (CGRP) lateral parabrachial nucleus (LPBN) neurons and assess their role in amylin's and sCT's ability to decrease food intake in mice. In addition, to test the involvement of LPBN CGRP neuropeptidergic signaling in the mediation of amylin and sCT's effects, a LPBN site-specific knockdown was performed in rats. To deeper investigate whether the greater anorectic effect of sCT compared to amylin is due do the recruitment of additional neuronal pathways related to malaise multiple and distinct animal models tested whether amylin and sCT induce conditioned avoidance, nausea, emesis, and conditioned affective taste aversion.. Our results indicate that permanent or transient inhibition of CGRP neurons in LPBN blunts sCT-, but not amylin-induced anorexia and neuronal activation. Importantly, sCT but not amylin induces behaviors indicative of malaise including conditioned affective aversion, nausea, emesis, and conditioned avoidance; the latter mediated by CGRP. Together, the present study highlights that although amylin and sCT comparably decrease food intake, sCT is distinctive from amylin in the activation of anorectic neuronal pathways associated with malaise.

Topics: Animals; Anorexia; Appetite Depressants; Calcitonin; Calcitonin Gene-Related Peptide; Islet Amyloid Polypeptide; Mice; Nausea; Neurons; Rats; Vomiting

Topics: Adrenergic alpha-Agonists; Amylin Receptor Agonists; Animals; Anorexia; Calcitonin; Eating; Islet Amyloid Polypeptide; Male; Neurons; Norepinephrine; Parabrachial Nucleus; Rats; Rats, Sprague-Dawley

In the present study, the effects of peripherally administered amylin and of the amylin-related peptide salmon calcitonin (sCT) on food and water intake was tested for the first time in pygmy goats. In the first series of experiments, the effect of amylin on food (0.5, 1.0 and 2.0 microg/kg b.wt.) and water (2.0 microg/kg) intake was tested. In the second series of experiments, the effect of sCT on food intake (1.0 microg/kg) was tested under ad libitum feeding conditions or after 14 h food deprivation. The relationship of dose on the effect of sCT (0.1, 0.5 and 1.0 microg/kg) on food and water intake was also tested. Finally, the effect of a low dose (0.1 sCT microg/kg) on water intake was also investigated during food withdrawal. We showed for the first time an anorexigenic effect of the satiety peptide amylin (2.0 microg/kg) in ruminants, which was characterized by a reduction in meal size. In pygmy goats, the administration of the three doses of sCT induced an anorexigenic effect, which was larger and of longer duration when compared with amylin, although the anorexigenic effect of the lowest dose never reached significance. This effect was not dose dependent and was partly due to a reduction in meal size and partly to a prolongation of the interval between meals. The anorexigenic effect of sCT was accompanied by a reduced water intake, probably due to reduced prandial drinking. Furthermore, the low dose of sCT (0.1 microg/kg) was dipsogenic during food withdrawal.

Topics: Amyloid; Animals; Anorexia; Anti-Ulcer Agents; Calcitonin; Dose-Response Relationship, Drug; Drinking; Drinking Behavior; Eating; Feeding Behavior; Food Deprivation; Goats; Islet Amyloid Polypeptide; Salmon; Subfornical Organ

We investigated the role of histamine H1 receptors in mediating the anorectic effect of intraperitoneally injected amylin (5 and 20 microg/kg), the amylin agonist salmon calcitonin (sCT; 10 microg/kg), leptin (1.3 mg/kg), and cholecystokinin (CCK; 20 microg/kg). The experiments were performed with mice lacking functional H1 receptors (H1Rko) and wild-type (WT) controls. The mice were also injected with the H3 antagonist thioperamide (20 mg/kg), which reduces feeding by enhancing the release of endogenous histamine through presynaptic H3 receptors. The feeding-suppressive effect of thioperamide was abolished in H1Rko mice. The anorectic effects of amylin and sCT were significantly reduced in 12-h food-deprived H1Rko mice compared with WT mice [1-h food intake: WT-NaCl 0.51 +/- 0.05 g vs. WT-amylin (5 microg/kg) 0.30 +/- 0.06 g (P < 0.01); H1Rko-NaCl 0.45 +/- 0.05 g vs. H1Rko-amylin 0.40 +/- 0.04 g; WT-NaCl 0.40 +/- 0.09 g vs. WT-sCT (10 microg/kg) 0.14 +/- 0.10 g (P < 0.05); H1Rko-NaCl 0.44 +/- 0.08 g vs. H1Rko-sCT 0.50 +/- 0.06 g]. The anorectic effect of leptin was absent in ad libitum-fed H1Rko mice, whereas CCK equally reduced feeding in WT and H1Rko animals. This suggests that the histaminergic system is involved in mediating the anorectic effects of peripheral amylin and sCT via histamine H1 receptors. The same applies to leptin but not to CCK. H1Rko mice showed significantly increased body weight gain compared with WT mice, supporting the role of endogenous histamine in the regulation of feeding and body weight.

Topics: Amyloid; Animals; Anorexia; Body Weight; Calcitonin; Cholecystokinin; Eating; Histamine Antagonists; Islet Amyloid Polypeptide; Leptin; Male; Mice; Mice, Knockout; Pancreas; Piperidines; Receptors, Histamine H1

A new analog of salmon calcitonin (N alpha-propionyl Di-Ala1,7,des-Leu19 sCT; RG-12851; here termed CTR), which lacks the ring structure of native calcitonin, was tested for biological activity in several in vitro and in vivo assay systems. The analog (CTR) and salmon calcitonin (sCT) stimulated kidney cell adenylate cyclase activity and inhibited bone resorption in organ cultures of fetal rat long bones with similar potencies and efficacies. Furthermore, CTR and sCT, at similar doses, induced comparable hypocalcemic responses in mice following sc injection or infusions. However, unlike sCT, CTR did not induce anorexia and weight loss in rats following sc injection. These data suggest that the ring structure of sCT may be important for the anorexigenic effect but is not required for effect on bone resorption or calcium homeostasis. Clinical studies appear warranted as, potentially, CTR might induce fewer side effects than does sCT.

Topics: Adenylyl Cyclases; Animals; Anorexia; Body Weight; Bone Resorption; Calcitonin; Cyclization; Eating; Feeding and Eating Disorders; Hypocalcemia; Kidney; Male; Mice; Mice, Inbred ICR; Organ Culture Techniques; Rats; Structure-Activity Relationship