Journal article
The Brainstem BBSome Regulates Glucose Homeostasis and Lean Mass in a State-Dependent Manner
Molecular metabolism (Germany), Vol.100, 102222
10/2025
DOI: 10.1016/j.molmet.2025.102222
PMCID: PMC12361606
PMID: 40744313
Abstract
Obesity disrupts metabolic homeostasis through changes in brain function. Hypothalamic cilia and associated proteins, such as the BBSome, a protein complex composed of eight Bardet-Biedl syndrome (BBS) proteins, have been implicated in metabolic regulation and disorders. Here, we investigated the significance of brainstem cilia and the BBSome for energy balance and glucose homeostasis METHODS: Primary cilia were assessed by immunofluorescence and confocal imaging, and brainstem neuron transcriptomes were analyzed using single-cell RNA sequencing. Mice with Phox2b-specific deletion of Ift88 or Bbs1 were studied under control or high-fat diets. Metabolic tests, insulin signaling, nerve recordings, and viral techniques were used to evaluate the impact of cilia or Bbs1 disruption.
We found that diet-induced obese mice display increased primary cilia length in the nucleus tractus solitarius. Single cell RNAseq revealed that cilia related genes are enriched in glutamatergic dorsal vagal complex (DVC) neurons expressing Phox2b. Primary cilia deletion in Phox2b neurons (Phox2b
/Ift88
) caused a mild weight reduction during adolescence without altering metabolic homeostasis during adulthood. We next investigated the brainstem BBSome using Phox2b
/Bbs1
mice, which exhibited reduced adolescent lean mass gain but normal adult body weight. Surprisingly, these mice developed glucose intolerance and elevated fasting glucose associated with contrasting changes in hepatic sympathetic and parasympathetic activity, pointing to autonomic imbalance as a cause of glucose dysregulation. Targeted BBSome disruption in the DVC replicated elevations in fasting glucose and chemogenetic DVC Phox2b neuron activation attenuated hyperglycemia during glucose tolerance test and suppressed hepatic sympathetic nerve activity. Interestingly, diet-induced obese Phox2b
/Bbs1
mice exhibited lower lean mass and a paradoxical improvement in glucose tolerance despite insulin resistance, suggesting a complex role for the brainstem BBSome in obesity-associated metabolic dysfunction.
Our findings highlight novel brainstem mechanisms regulating metabolic homeostasis and distinct roles for primary cilia and the BBSome in glucose regulation and lean mass.
Details
- Title: Subtitle
- The Brainstem BBSome Regulates Glucose Homeostasis and Lean Mass in a State-Dependent Manner
- Creators
- Connor Laule - University of IowaDeng-Fu GuoYuying Zhao - University of IowaPaul A Williams - University of IowaDonald A Morgan - University of IowaYounes Rouabhi - University of IowaMiriam McDonough - University of IowaTrevor Butler - University of IowaJon Resch - University of IowaKamal Rahmouni - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Molecular metabolism (Germany), Vol.100, 102222
- DOI
- 10.1016/j.molmet.2025.102222
- PMID
- 40744313
- PMCID
- PMC12361606
- NLM abbreviation
- Mol Metab
- ISSN
- 2212-8778
- eISSN
- 2212-8778
- Publisher
- ELSEVIER
- Grant note
- National Institutes of Health: GM067795, HL168820, R01 HL162773, R01 HL172944 Department of Veterans Affairs: BX004249, BX006040 University of Iowa Vice President for ResearchCarver College of Medicine
This work was supported by National Institutes of Health (Grants GM067795 and HL168820 to C.L and R01 HL162773 and R01 HL172944 to K.R.) and the Department of Veterans Affairs (BX004249 and BX006040 to K.R.) . The University of Iowa Central Microscopy Research Facility is a core resource supported by the University of Iowa Vice President for Research and the Carver College of Medicine.
- Language
- English
- Electronic publication date
- 07/29/2025
- Date published
- 10/2025
- Academic Unit
- Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984917085102771
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