Transcriptome-guided GLP-1 receptor therapy rescues metabolic and behavioral disruptions in a Bardet-Biedl Syndrome mouse model

Arashdeep Singh; Naila Haq; Mingxin Yang; Shelby Luckey; Samira Mansouri; Martha Campbell-Thompson; Lei Jin; Sofia Christou-Savina; Guillaume de Lartigue

doi:10.1172/JCI184636

Transcriptome-guided GLP-1 receptor therapy rescues metabolic and behavioral disruptions in a Bardet-Biedl Syndrome mouse model

Arashdeep Singh,¹ Naila Haq,² Mingxin Yang,³ Shelby Luckey,⁴ Samira Mansouri,⁵ Martha Campbell-Thompson,⁶ Lei Jin,⁵ Sofia Christou-Savina,² and Guillaume de Lartigue¹

Published April 15, 2025 - More info

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Abstract

Bardet-Biedl Syndrome (BBS), a ciliopathy characterized by obesity, hyperphagia, and learning deficits, arises from mutations in BBS genes. More exacerbated symptoms occur with mutations in genes encoding the BBSome, a complex regulating primary cilia function. We investigated the mechanisms underlying BBS-induced obesity using a novel BBS5 knockout (BBS5-/-) mouse model. BBS5-/- mice displayed hyperphagia, learning deficits, glucose/insulin intolerance, and disrupted metabolic hormones, phenocopying human BBS. They displayed an unique immunophenotype in white adipose tissue with increased proinflammatory macrophages and dysfunctional regulatory T cells, suggesting a distinct mechanism for adiposity compared to typical obesity models. Additionally, BBS5-/- mice exhibited pancreatic islet hyperplasia but failed to normalize blood glucose, suggesting defective insulin action. Hypothalamic transcriptomics revealed dysregulated endocrine signaling pathways with functional analyses confirming defects in insulin, leptin, and cholecystokinin (CCK) signalling, while preserving glucagon-like peptide-1 receptor (GLP-1R) responsiveness. Notably, treatment with a GLP-1R agonist effectively alleviated hyperphagia, body weight gain, improved glucose tolerance, and circulating metabolic hormones in BBS5-/- mice. This study establishes BBS5-/- mice as a valuable translational model of BBS to understand the pathogenesis and develop novel treatments. Our findings highlight the therapeutic potential of GLP-1R agonists for managing BBS-associated metabolic dysregulation, warranting further investigation for clinical application.

Transcriptome-guided GLP-1 receptor therapy rescues metabolic and behavioral disruptions in a Bardet-Biedl Syndrome mouse model

Arashdeep Singh,¹ Naila Haq,² Mingxin Yang,³ Shelby Luckey,⁴ Samira Mansouri,⁵ Martha Campbell-Thompson,⁶ Lei Jin,⁵ Sofia Christou-Savina,² and Guillaume de Lartigue¹

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Transcriptome-guided GLP-1 receptor therapy rescues metabolic and behavioral disruptions in a Bardet-Biedl Syndrome mouse model

Arashdeep Singh,1 Naila Haq,2 Mingxin Yang,3 Shelby Luckey,4 Samira Mansouri,5 Martha Campbell-Thompson,6 Lei Jin,5 Sofia Christou-Savina,2 and Guillaume de Lartigue1

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Arashdeep Singh,¹ Naila Haq,² Mingxin Yang,³ Shelby Luckey,⁴ Samira Mansouri,⁵ Martha Campbell-Thompson,⁶ Lei Jin,⁵ Sofia Christou-Savina,² and Guillaume de Lartigue¹