Lay summary
We have discovered a ‘hyperactive’ CALCRL gene variant that is enriched in people of Māori/Pacific descent and is linked to metabolic disease, including raised blood sugar levels. CALCRL encodes a receptor that binds the peptide hormone adrenomedullin (ADM) and regulates blood pressure and fat homeostasis. Rats carrying the variant show a phenotype of increased nitric oxide (NO) production, accompanied by abnormal visceral (‘bad’) fat accumulation, impaired fat breakdown and inflammation. We hypothesise that an overly activated ADM-CALCRL-NO axis promotes visceral fat accumulation, via inhibition of lipolysis, and this increases the severity of metabolic disease, due to known effects of inflammation on insulin resistance. Our hypothesis will be tested in rats fed a high fat ‘Western diet’ to induce metabolic disease and by mechanistic studies of lipolysis in rat and human adipocytes. This work paves the way to developing precision medicine strategies for Māori and Pacific people, with significant health benefits.