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
Arashdeep Singh, Naila Haq, Mingxin Yang, Shelby Luckey, Samira Mansouri, Martha Campbell-Thompson, Lei Jin, Sofia Christou-Savina, Guillaume de Lartigue
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Research Article Endocrinology Metabolism

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

Abstract

Bardet-Biedl syndrome (BBS), a ciliopathy characterized by obesity, hyperphagia, and learning deficits, arises from mutations in Bbs genes. 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 Bbs5-knockout (Bbs5–/–) mouse model. Bbs5–/– mice were characterized by hyperphagia, learning deficits, glucose/insulin intolerance, and disrupted metabolic hormones, phenocopying human BBS. White adipose tissue in these mice had a unique immunophenotype, with increased proinflammatory macrophages and dysfunctional Tregs, suggesting a mechanism for adiposity distinct from those of typical obesity models. Additionally, Bbs5–/– mice exhibited pancreatic islet hyperplasia but failed to normalize blood glucose, suggesting defective insulin action. Hypothalamic transcriptomics revealed dysregulation of endocrine signaling pathways, with functional analyses confirming defects in insulin, leptin, and cholecystokinin (CCK) signaling, while glucagon-like peptide-1 receptor (GLP-1R) responsiveness was preserved. Notably, treatment with a GLP-1RA effectively alleviated hyperphagia and body weight gain, improved glucose tolerance, and regulated circulating metabolic hormones in Bbs5–/– mice. This study suggests that Bbs5–/– mice represent a valuable translational model of BBS for understanding pathogenesis and developing better treatments. Our findings highlight the therapeutic potential of GLP-1RAs for managing BBS-associated metabolic dysregulation, indicating that further investigation for clinical application is warranted.

Authors

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

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Figure 4

Hypothalamic RNA transcriptomics predicts leptin and CCK resistance but retention of GLP-1 response in male Bbs5-null mice.

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Hypothalamic RNA transcriptomics predicts leptin and CCK resistance but ...
(A) Volcano plot of differential expression changes, plotting the log fold change (FC) in receptors in the hypothalamus in 12-week-old male Bbs5–/– relative to WT mice (n = 2–3 per group). Red dots represent significant differences; black, nonsignificant. (B) Schematic experimental design to determine anorexigenic effects of leptin, CCK-8, and GLP-1RA exendin-4 in overnight-fasted male WT and Bbs5–/– mice. (C and D) The effect of i.p. leptin (red, 2 mg/kg body weight) or vehicle (black) injection on cumulative ad libitum food intake in 12- to 18-week-old male WT (C) and Bbs5–/– (D) mice over 24 hours (n = 9 per group). (E and F) Body weight gain in WT (E) and Bbs5–/– (F) mice at 24 and 36 hours after leptin injections. (G and H) Effect of i.p. CCK-8 (orange, 2 μg/kg body weight) or vehicle (black) injection on cumulative ad libitum food intake in 12- to 18-week-old male WT (G) and Bbs5–/– (H) mice over 24 hours (n = 7–9 per group). (I and J) Food intake suppression after 2 (I) or 11 hours (J) in 12- to 18-week-old male WT and Bbs5–/– mice following CCK-8 (2 or 4 μg/kg body weight) relative to saline injection (n = 7–9 per group). (K and L) Effect of i.p. exendin-4 (purple, 1 μg/kg body weight) or vehicle (black) injection on cumulative ad libitum food intake in 12- to 18-week-old male WT (K) and Bbs5–/– (L) mice over 24 hours (n = 8 per group). (M and N) Food intake suppression after 2 (M) or 11 hours (N) in 12- to 18-week-old male WT and Bbs5–/– mice following exendin-4 (0.1 or 1 or 2 μg/kg body weight) relative to saline injection (n = 8 per group). Data in C–N were analyzed using repeated-measure 2-way ANOVA with Benjamini, Krieger, and Yekutieli post hoc test (FDR = 0.05) to compare individual time points. Data are mean ± SEM from chow-fed WT (vehicle or drug treated) and Bbs5–/– (vehicle or drug treated) male mice; nd, no discovery; *P < 0.05; **P < 0.01; ***P < 0.001.