Tuning Adipocyte Size and Obesity through SWELL1

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Project Summary Healthy adipose tissue expansion is necessary for maintaining metabolic health in the setting of over-nutrition – a situation that is increasingly relevant in the US, as the incidence of obesity is estimated at 33% of the US population. Therefore, elucidating the fundamental nutrient sensing mechanisms that regulate adipocyte expansion is critical for understanding, and ultimately treating, the negative metabolic consequences of obesity. We previously identified Leucine Rich Repeat Containing 8A (LRRC8a or SWELL1), a newly discovered essential component of the volume-regulated anion channel (VRAC), as a novel volume-sensing regulator of both insulin sensitivity and insulin secretion. We and others find that SWELL1 activity and protein expression is reduced in metabolically unhealthy obese mice and humans – suggesting that reduced multi-organ SWELL1 activity/expression contributes to obesity-induced metabolic syndrome. Our group has biochemical, patch- clamp and imaging evidence that SWELL1 channel complexes are also expressed and functional in lysosomes. Given that lysosomes are signaling hubs that integrate nutrient sensing and AKT-mTOR signaling, we hypothesize that lysosomal SWELL1-LRRC8 channels participate in cellular nutrient sensing by activating in response to increases in intraluminal lysosomal leucine, and that this signaling mechanism is dysregulated in the setting of obesity-induced diabetes and insulin resistance. To test this hypothesis, we combine unique reagents and innovative methods from the Diwan (lysosomal signaling), Xu (lysosomal patch-clamp), and Held (mass spectrometry) laboratories, with our expertise in SWELL1 signaling, and access to human adipose tissue samples from highly phenotyped metabolically healthy and unhealthy humans (Klein laboratory). Our objective is to understand the mechanisms of plasma membrane and lysosomal SWELL1 (Lyso- SWELL1) nutrient sensing and how it is dysregulated in disease states, including obesity-induced glucose intolerance and insulin resistance. The rationale for these studies is that delineating the contribution of SWELL1 to lysosomal nutrient sensing and mTORC1 activation will advance our understanding of a fundamental cellular signaling mechanism and guide innovative therapeutic approaches for patients with prediabetes and diabetes. We propose the following AIMs: · AIM#1: Delineate the mechanisms of plasma membrane versus lysosomal SWELL1 signaling to AKT- AMPK-mTOR signaling in adipocytes · AIM#2: Examine the contribution of SWELL1 signaling in vivo in the setting of obesity in mice and humans The knowledge gained from these studies will delineate a novel lysosomal ion channel signaling pathway that regulates adipocyte growth and systemic dysglycemia in obesity, and inform therapeutic strategies currently underway to modulate SWELL1 signaling for the treatment of obesity-induced metabolic syndrome.