Cover Story Current Issue
Despite intensive drug development efforts and public health initiatives, obesity is increasing in incidence and predicted to affect over 50% of all adults worldwide by 2035. Being chronically overweight increases the risk of serious disease co-morbidities that, in turn, increase mortality and healthcare costs. Behavioral approaches to combat obesity, such as diet and exercise, rarely produce lasting weight loss commonly due to compensatory hyperphagia and hypometabolism. These limitations have stimulated interest in pharmacotherapies that target gut-derived peptide hormones involved in the regulation of energy homeostasis, such as PYY, GIP, CCK, and GLP-1. These peptides are secreted by different enteroendocrine cells distributed throughout the intestine in response to food intake, subsequently enhancing satiation signaling and ultimately promotes meal termination. However, a major challenge of FDA-approved and experimental weight-loss medications that target GI-derived satiation signals is the frequent occurrence of nausea and vomiting.
Current Issue
The brainstem BBSome regulates glucose homeostasis and lean mass in a state-dependent manner
The brainstem BBSome regulates glucose homeostasis and lean mass in a state-dependent manner
Objective
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.
Results
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 (Phox2bCre/Ift88 fl/fl) caused a mild weight reduction during adolescence without altering metabolic homeostasis during adulthood. We next investigated the brainstem BBSome using Phox2bCre/Bbs1fl/fl 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 Phox2bCre/Bbs1fl/fl 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.
Conclusions
Our findings highlight novel brainstem mechanisms regulating metabolic homeostasis and distinct roles for primary cilia and the BBSome in glucose regulation and lean mass.
Articles in Press
The brainstem BBSome regulates glucose homeostasis and lean mass in a state-dependent manner
The brainstem BBSome regulates glucose homeostasis and lean mass in a state-dependent manner
Objective
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.
Results
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 (Phox2bCre/Ift88 fl/fl) caused a mild weight reduction during adolescence without altering metabolic homeostasis during adulthood. We next investigated the brainstem BBSome using Phox2bCre/Bbs1fl/fl 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 Phox2bCre/Bbs1fl/fl 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.
Conclusions
Our findings highlight novel brainstem mechanisms regulating metabolic homeostasis and distinct roles for primary cilia and the BBSome in glucose regulation and lean mass.
SAVE THE DATE!
13th
Helmholtz Diabetes Conference
Munich, 21-23. Sep 2026
2024 impact factor: 6.6
You are what you eat
Here is a video of Vimeo. When the iframes is activated, a connection to Vimeo is established and, if necessary, cookies from Vimeo are also used. For further information on cookies policy click here.