oa Expression and regulation of brown adipose tissue activity by renalase

Obesity is an established risk factor for hypertension. About 1 billion adults are overweight globally and numbers appear to be increasing. Stimulating endogenous activation of brown adipose tissue (BAT) mass that has unprecedented metabolic capacity can combat obesity, reverse insulin resistance and reduce comorbidities. Renalase is a recently discovered flavin adenine dinucleotide (FAD)-dependent oxidase, predominantly secreted into the circulation from the kidney and regulates catecholamine degradation and metabolism. Renalase gene is also present in heart muscle, skeletal muscle and liver cells in humans, and in mouse testicles. Four isoforms of renalase gene has been identified in humans (hRenalase1 to hRenalase4), however only hRenalase1 is detected in human blood suggesting that hRenalase2 to 4 may have alternative function. Unlike the classical amine oxidases which are expressed intracellularly, renalase is present intracellularly and is also secreted into the circulation. Circulating renalase appears to mirror sympathetic tone, a brief increase in catecholamines results in significant up-regulation of renalase synthesis, secretion and activity. Catecholamines are principle activators of BAT thermogenesis and angiogenesis both in rodents and humans. Characterization studies in renalase‐knockout mice shows that these mice have about 25% reduced body weight compared to control, increased circulating catecholamines, are hypertensive, and have cardiovascular defects. Renalase‐knockout mice have activated sympathetic system and possibly have increased BAT activity as a result of elevated catecholamine's in the circulation. Our findings in adipose tissue demonstrate that the renalase gene and protein is expressed in both white and brown adipose tissue depots. Expression of renalase increases in BAT of mice during non-shivering thermogenesis and in diet-induced obese mice. The expression of renalase gene, protein and secretion are significantly higher in differentiated mature brown and white adipocytes compared to preadipocytes. Stimulation of mature brown adipocytes with norepinephrine, the main catecholamine released during cold induced non-shivering thermogenesis in vivo, results in significant increase in renalase expression suggesting the importance of renalase in non-shivering thermogenesis. In white adipocytes, renalase expression is up-regulated in response to treatment with obesity linked adipokines, specifically, leptin and insulin. We report renalase as a novel adipokine expressed and secreted from both BAT and WAT. From our preliminary findings and observations in renalase knockout mice having increased sympathetic activity and circulating catecholamines, we hypothesise "renalase regulates BAT development, thermogenesis and metabolism". Therefore further studies are needed in renalase knockout mice to understand the role of renalase in adipose tissue metabolism which could provide us clues on its role in obesity and insulin resistance. Understanding the mechanisms of renalase action may provide translational data that underpins future treatment in obesity associated cardio-metabolic complications.