The exact mechanisms underlying the metabolic effects of bariatric surgery remain unclear. Here, we demonstrate, using a combination of direct and indirect calorimetry, an increase in total resting metabolic rate (RMR) and specifically anaerobic RMR after Roux-en-Y gastric bypass (RYGB), but not sleeve gastrectomy (SG). We also show an RYGB-specific increase in splanchnic sympathetic nerve activity and “browning” of visceral mesenteric fat. Consequently, selective splanchnic denervation abolishes all beneficial metabolic outcomes of gastric bypass that involve changes in the endocannabinoid signaling within the small intestine. Furthermore, we demonstrate that administration of rimonabant, an endocannabinoid receptor-1 (CB1) inverse agonist, to obese mice mimics RYGB-specific effects on energy balance and splanchnic nerve activity. On the other hand, arachidonoylethanolamide (AEA), a CB1 agonist, attenuates the weight loss and metabolic signature of this procedure. These findings identify CB1 as a key player in energy regulation post-RYGB via a pathway involving the sympathetic nervous system.

Bardet-Biedl syndrome (BBS) is a rare hereditary autosomal recessive disease associated with several features including obesity, hypertension, and renal abnormalities. The underlying mechanisms of renal defects associated with BBS remain poorly defined. We examined the histological, molecular, and functional renal changes in BBS mouse models that have features of the human disorder. Interestingly, obese hypertensive Bbs4 ^−/− mice exhibited inflammatory infiltration and renal cysts, whereas the obese normotensive Bbs2 ^−/− mice had only minor inflammatory infiltration. Accordingly, the expression level of inducible nitric oxide synthase was elevated in the kidney of both BBS mice with a more marked increase in Bbs4 ^−/− mice. In contrast, endothelial nitric oxide synthase expression was decreased in Bbs4 ^−/−, but not Bbs2 ^−/−, mice. Similarly, the expression levels of transient receptor potential vanilloid 1 and 4 channels as well as β- and γ-subunits of epithelial Na channel were significantly reduced only in the kidney of Bbs4 ^−/− mice. Metabolic studies revealed changes in urine output and urinary concentrations of creatinine, blood urea nitrogen, sodium, and potassium with a more pronounced effect in Bbs4 ^−/− mice. Finally, we found that calorie restriction which prevented obesity in BBS mice reversed the morphological and molecular changes found in Bbs2 ^−/− and Bbs4 ^−/− mice, indicating the kidney abnormalities associated with BBS are obesity related. These findings extend our understanding of the function of BBS proteins and emphasize the importance of these proteins in renal physiology.

Endothelial cells that line the entire vascular system play a pivotal role in the control of various physiological processes, including metabolism. Additionally, endothelial dysfunction is associated with many pathological conditions, including obesity. Here, we assessed the role of the BBSome, a protein complex composed of eight Bardet-Biedl syndrome (BBS) proteins in endothelial cells. We studied the effects of BBSome disruption in endothelial cells on vascular function, body weight, glucose homeostasis, and the liver and retina. For this, we generated mice with selective BBSome disruption in endothelial cells through Bbs1 gene deletion. We found that endothelial cell-specific BBSome disruption causes endothelial dysfunction, as indicated by the impaired acetylcholine-induced vasorelaxation in both the aorta and mesenteric artery. This was associated with an increase in the contractile response to thromboxane A2 receptor agonist (U46619) in the mesenteric artery. Mechanistically, we demonstrated that mice lacking the Bbs1 gene in endothelial cells show elevated vascular angiotensinogen gene expression, implicating renin-angiotensin system activation in the vascular changes evoked by endothelial BBSome deficiency. Strikingly, our data indicate that endothelial BBSome deficiency increases body weight and fat mass and causes hepatosteatosis along with alterations in hepatic expression of lipid metabolism-related genes and metabolomics profile. In addition, electroretinogram and optical coherence tomography analyses revealed functional and structural abnormalities in the retina, evoked by absence of the endothelial BBSome. Our findings demonstrate that the BBSome in endothelial cells is required for the regulation of vascular function, adiposity, hepatic lipid metabolism, and retinal function.

The autonomic networks of the central nervous system tightly coordinate metabolic and cardiovascular functions. The frequent coexistence of metabolic and cardiovascular disorders suggests cross talk between neural circuits governing energy balance and cardiovascular regulation. In this study, we used trans-neuronal tracing to define the higher-order neurons involved in the coordination of cardiometabolic regulation in mice. We identified several nuclei that contain neurons associated with a cardiovascular organ (kidney) and metabolic tissues (brown adipose tissue [BAT] or liver), with substantial overlap across regions. Co-projecting neurons (kidney-BAT or kidney-liver) were observed in areas including the cortical, hypothalamic, midbrain, and brainstem regions. Analysis of soma size revealed regional and organ-specific differences, with some nuclei exhibiting multiple morphological phenotypes. Notably, soma size distributions differed significantly between kidney- and BAT-projecting neurons in the motor cortex and locus coeruleus, but not in the paraventricular nucleus or lateral hypothalamus. These findings indicate that while cardiometabolic control involves overlapping neuronal populations, morphological specialization may distinguish neurons regulating cardiovascular versus metabolic functions. Together, this work provides anatomical evidence supporting the integrative organization of autonomic networks that coordinate cardiovascular and metabolic regulation.

This study combines AI modeling and experimental validation to define key structural features and receptor interactions of the BBSome complex. The analysis identifies BBS1 and BBS9 as central hubs, reveals how the BBS1 ^M390R mutation destabilizes the complex, and uncovers novel contacts with various receptors including those involved in metabolic regulation. These findings provide a predictive framework linking BBSome structure to ciliary signaling and metabolic regulation in Bardet–Biedl syndrome.