Abstract
The hormones amylin and calcitonin interact with receptors within the same family to exert their effects on the human organism. Calcitonin, derived from thyroid C cells, is known for its inhibitory effect on osteoclasts. Calcitonin of mammalian origin promotes insulin sensitivity, while the more potent calcitonin extracted from salmon additionally inhibits gastric emptying, promotes gallbladder relaxation, increases energy expenditure and induces satiety as well as weight loss. Amylin, derived from pancreatic beta cells, regulates plasma glucose by delaying gastric emptying after meal ingestion, and modulates glucagon secretion and central satiety signals in the brain. Thus, both hormones seem to have metabolic effects of relevance in the context of non-alcoholic fatty liver disease (NAFLD) and other metabolic diseases. In rats, studies with dual amylin and calcitonin receptor agonists have demonstrated robust body weight loss, improved glucose tolerance and a decreased deposition of fat in liver tissue beyond what is observed after a body weight loss. The translational aspects of these preclinical data currently remain unknown. Here, we describe the physiology, pathophysiology, and pharmacological effects of amylin and calcitonin and review preclinical and clinical findings alluding to the future potential of amylin and calcitonin-based drugs for the treatment of obesity and NAFLD.
Highlights
Hepatic steatosis is widely regarded the hepatic manifestation of the metabolic syndrome [1]
The C-terminus is amidated (-NH2) in all peptides, whereas only novel dual amylin and calcitonin receptor agonist (DACRA) compounds have an N-terminus acetylation (Ac-) for enhanced stability. rAMY, rat amylin; hAMY, human amylin; sCT, salmon calcitonin; hCT, human calcitonin; eCT, eel calcitonin, blue indicates amino acid sequence derived from human amylin; green indicates amino acid sequence derived from salmon calcitonin; yellow indicates amino acids derived from rat amylin; gray indicates amino acid sequence derived from human calcitonin; red indicates amino acids derived from eel calcitonin
The tissue distribution of the amylin receptor complex is difficult to describe for a number of reasons: 1) the calcitonin receptor has two subtypes which interact with RAMPs, 2) RAMPs are associated with other receptors than the amylin receptor complex, and 3) there is a lack of selective pharmacological tools and antibodies to target specific amylin (RAMP/calcitonin) receptor complexes [26]
Summary
Hepatic steatosis is widely regarded the hepatic manifestation of the metabolic syndrome [1]. Body weight loss is currently the most effective strategy to improve both measures of steatosis and NAFLD outcomes [5] and several anti-obesity medications in clinical development have demonstrated improvements with regards to liver fat content [6, 7]. The term “metabolic-associated fatty liver disease (MASH)” has been proposed as a unifying definition of hepatic steatosis in individuals with overweight/obesity, metabolic dysregulation and/or manifest type 2 diabetes [16]. This definition recognizes the importance of obesity and insulin resistance, rather than the absence of excessive alcohol consumption, as a causal factor for the development of hepatic steatosis. Stimulating the amylin receptor complex increases the Frontiers in Endocrinology | www.frontiersin.org
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