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Commentary
Open Access | 
10.1172/JCI191822
Should GLP-1 receptor agonist therapy be used to treat obesity in Bardet-Biedl syndrome?
Jeremy W. Tomlinson
Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, United Kingdom.
Address correspondence to: Jeremy Tomlinson, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, United Kingdom. Phone: 44.0.1865.857359; Email: Jeremy.tomlinson@ocdem.ox.ac.uk
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Published June 16, 2025 - More info
J Clin Invest. 2025;135(12):e191822. https://doi.org/10.1172/JCI191822.
© 2025 Tomlinson This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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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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A model with leptin resistance and GLP-1 sensitivity
As reported in the current issue of the JCI, Singh et al. (2) have developed a mouse model of BBS with genetic deletion of the Bbs5 gene on a C57BL/6J background. Importantly, the mice displayed many of the features that are commonly observed in patients with BBS, including the development of obesity with associated hyperphagia. In addition, the mice showed evidence of learning difficulties, alongside metabolic disturbance with impaired glucose tolerance, hyperinsulinemia, and associated pancreatic islet hyperplasia. Circulating hyperleptinemia, indicative of leptin resistance, was also noted. There was no evidence of a sexually dimorphic phenotype. Detailed transcriptomic analysis identified hypothalamic signatures of transcription factors that have the potential to affect satiety signaling, notably leptin; and indeed, administration of exogenous leptin did not result in weight loss or appetite suppression in the Bbs5–/– mice, contrasting with observations in WT controls (Figure 1).
Figure 1Bbs5–/– mice have an adverse metabolic phenotype. Mice lacking Bbs5 show defects in appetite signaling, immune cell dysregulation in epididymal white adipose tissue (eWAT), and pancreatic islet hyperplasia, driving increased food intake, obesity, and insulin resistance. Response to exogenous GLP-1 administration is preserved, leading to improvements in metabolic phenotype. DEG, differentially expressed gene.
In the majority of clinical phenotyping studies involving patients with BBS, there is evidence of elevated leptin levels (3, 4). However, reflecting some of the challenges in undertaking metabolic phenotyping in patients with BBS,which often include small samples sizes, leptin levels above those in BMI-matched control individuals have not always been observed (5).
Many published rodent models of BBS, including Bbs2, Bbs4, and Bbs6 global-knockout mice, as well as a conditional neuron-specific model of BBS1 deficiency, have elevated circulating leptin levels and impaired leptin action (6). However, there are conflicting data in the published literature: Some studies using mice with deletion of Bbs4 and Bbs5 have shown a normal leptin response in the absence of obesity or when food is restricted. It is plausible, therefore, that the leptin resistance observed in these models is due to the acquired increase in weight rather than being a specific consequence of the BBS gene deletion (7). Other studies have shown that Bbs2-, Bbs4-, and Bbs6-knockout mice are leptin resistant, independent of obesity; and in these models, hypothalamic leptin receptor signaling was impaired (8).
One important consideration across all the models of BBS is how well they recapitulate the human phenotype of disease. These model-based data are challenging to ascertain, as detailed and extensive metabolic phenotyping has not been extensively undertaken in patients with BBS, and a stratified analysis by genotype is almost completely lacking. That said, published data would suggest that the most common genetic abnormality underpinning BBS, within the BBS1 gene, may be associated with a milder metabolic phenotype in comparison with other genotypes (9). Detailed metabolic phenotyping in patients with BBS5 has not been performed, and therefore it is impossible to tell whether this model truly represents the clinical picture of BBS. However, obesity and metabolic dysfunction are described in case reports of most (10–12) but not all (13) patients with BBS5 mutations.
In the article by Singh et al. (2), transcriptomic analysis of the hypothalamus yielded some interesting and perhaps surprising results. For example, the authors noted increased expression of the melanocortin-4 receptor (MC4R). While this observation may have been a little unexpected, it is of particular relevance in the context of BBS. Recently, the MC4R agonist setmelanotide has received FDA approval for the treatment of hyperphagia and obesity in adults and children with BBS. Published data suggest that alongside weight loss and hunger suppression, there is an associated improvement in quality of life for both patients and carers (14–16).
A key finding from Singh et al. (2) involves retained sensitivity to GLP-1 receptor agonist (GLP-1RA) therapy in the mouse model. There was an 8-fold elevation in hypothalamic expression of GLP-1R in Bbs5–/– mice. Circulating endogenous GLP-1 levels were not different from those in WT control animals, and this attribute has also been reflected in clinical studies, albeit in very small numbers in a pediatric population of patients with BBS (17). However, treatment of the Bbs5–/– mice with exogenous GLP-1RAs (i.e., exendin-4 and semaglutide) limited food intake, decreased weight, improved circulating hyperleptinemia, lowered circulating insulin levels, and improved glucose tolerance (2).
There are some limitations within the current study. In the absence of a weight-matched comparator, it is challenging to disentangle the specific contribution of the Bbs5 gene deletion over and above the impact of obesity. Similarly, a comparison of the effects on metabolic phenotype with GLP-1RA therapy in a matched obese model was lacking. Finally, of particular relevance to the authors’ observations with regard to increased hypothalamic expression of MC4R, an investigative arm exploring the use of setmelanotide would have been highly informative (2).
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