Ciliary signaling mechanisms regulating white adipose tissue expansion

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Project summary: More than 70% of adults in the USA are obese or overweight, and comorbidities, such as diabetes, pose a significant challenge to public health. In response to excess nutrients, white adipose tissue expands by both hypertrophy and de novo adipogenesis. Excessive hypertrophy is linked to insulin resistance, while mechanisms that promote adipogenesis can limit the pathogenic consequences of obesity. We recently discovered that pre- adipocytes express an antenna-like signaling organelle called the primary cilium, and that primary cilia are required for in vivo adipogenesis. We propose that primary cilia function as signaling hubs in pre-adipocytes, regulating their adipogenic potential, and hence, how white adipose tissue expands in response to caloric imbalance. Remarkably, we recently discovered that pre-adipocytes isolated from obese human and murine white adipose tissue have both fewer and shorter cilia compared to lean pre-adipocytes. To elucidate the functional importance of ciliary signaling in directing how white adipose tissue expands, we propose the following two aims: (Aim 1) Investigate how obesity affects pre-adipocyte ciliation and ciliary signaling. Pre-adipocytes in obese white adipose tissue are known to differentiate poorly due to a cell-intrinsic defect that decreases their adipogenic potential. This contributes to adipocyte hypertrophy, inflammation, and tissue dysfunction. We propose that the obese white adipose tissue microenvironment promotes pathogenic loss of pre-adipocyte primary cilia. This loss results in impairment of ciliary, pro-adipogenic signaling and decreased adipogenic potential, leading to hypertrophic expansion of white adipose tissue and contributing to impairments in glucose and lipid metabolism. Using a combination of molecular and cell biological techniques and mouse models, we will define the adipogenic signaling defects governed by obesity-induced ciliary shortening and loss, as well as the underlying mechanism. (Aim 2) Determine how human genetic mutations in ciliary genes lead to obesity and diabetes. Two ciliopathies are linked to obesity in patients, but the mutations drive opposing effects with regard to metabolic health. Both ciliopathy mutations alter the trafficking of ciliary cargo into and out of the primary cilium. We propose that these alterations modulate the composition of ciliary signaling pathways, altering the adipogenic potential of pre-adipocytes and how white adipose tissue expands. Together, experiments proposed in the two aims will establish the functional importance of pre-adipocyte cilia to white adipose tissue expansion. The proposed research constitutes a completely novel and innovative approach to identifying mechanisms underlying the loss of adipogenic potential of obese pre-adipocytes that drives pathogenesis.