We should not forget the potential off-target metabolic effects of CGRP inhibitors, say Christopher S Walker and Debbie L Hay of the School of Biological Sciences, The University of Auckland, New Zealand
The major concern when considering the possible off-target effects of blocking CGRP activity in migraine with small molecule antagonists or antibodies, appears to be possible cardiovascular effects.1 It is important to remember that CGRP has a long history and is reported to have pharmacological effects in numerous experimental paradigms, which extend beyond the cardiovascular system.2
A recent report by Liu et al highlights an element of CGRP biology that is worth discussing in the context of chronic CGRP blockade that would likely occur with the current suite of investigational drugs.3 The authors reported positive metabolic benefit of CGRP depletion, in the context of a mouse model that lacks CGRP: a CGRP knockout mouse.
Interestingly this study mirrors an earlier report published in 2010, which drew very similar conclusions.4 Both studies report that, when challenged with a high-fat diet, the CGRP knockout mice had lower body weight, adiposity and resistance to hepatic lipid accumulation. These are the only CGRP knockout studies reporting metabolic effects, but other work supports the conclusion that CGRP does have activity on the metabolic axis.
For example, there are studies showing a variety of metabolic effects, including that the CGRP antagonist CGRP8-37 affects metabolic health, that CGRP affects fat metabolism and that CGRP affects feeding behaviour.5-12 It is not clear which CGRP receptor(s) mediate these effects, nor if there is any metabolic effect of CGRP in humans. However, as clinical studies of CGRP blocking agents in migraine proceed, these other reported effects of the CGRP system should be kept in mind.
Professor Debbie Hay (University of Auckland, New Zealand)
Dr Christopher S Walker (University of Auckland, Auckland, New Zealand)
Contact: Debbie L Hay
- MaassenVanDenBrink A, Meijer J, Villalón CM, Ferrari MD. Wiping out CGRP: potential cardiovascular risks. Trends Pharmacol Sci 2016;37:779-88.
- Russell FA, King R, Smillie SJ, et al. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev 2014;94:1099-1142.
- Liu T, Kamiyoshi A, Sakurai T, et al. (Endogenous calcitonin gene-related peptide regulates lipid metabolism and energy homeostasis in male mice. Endocrinol 2017;158:1194-1206.
- Walker CS, Li X, Whiting L, et al. Mice lacking the neuropeptide α-calcitonin gene-related peptide are protected against diet-induced obesity. Endocrinol 2010;151:4257-69.
- Riera CE, Huising MO, Follett P, et al. TRPV1 pain receptors regulate longevity and metabolism by neuropeptide signaling. Cell 2014;157;1023-36.
- Roman CW, Derkach VA, Palmiter RD. Genetically and functionally defined NTS to PBN brain circuits mediating anorexia. Nature Comm 2016;7:11905.
- Danaher RN, Loomes K, Leonard BL, et al. Evidence that alpha-calcitonin gene-related peptide is a neurohormone that controls systemic lipid availability and utilization, Endocrinol 2008;149:154-60.
- Campos CA, Bowen AJ, Schwartz MW, Palmiter RD. Parabrachial CGRP neurons control meal termination. Cell Metab 2016;23:811-820.
- Carter ME, Soden ME, Zweifel LS, Palmiter RD. Genetic identification of a neural circuit that suppresses appetite. Nature 2013;503:111-14.
- Chatzipanteli K, Goldbergt RB, Howard GA, Roos BA. Calcitonin gene-related peptide is an adipose-tissue neuropeptide with lipolytic actions. Endocrinol Metab 1996;3:235-42.
- Dhillo WS, Small CJ, Jethwa PH, et al. Paraventricular nucleus administration of calcitonin gene-related peptide inhibits food intake and stimulates the hypothalamo-pituitary-adrenal axis. Endocrinol 2003;144:1420-5.
- Walker CS, Hay DL, Fitzpatrick SM, et al. 'α-Calcitonin gene related peptide (α-CGRP) mediated lipid mobilization in 3T3-L1 adipocytes. Peptides 2014;58:14-19.