Dataset Information

BBSome ablation in SF1 neurons causes obesity without comorbidities.

ABSTRACT:

Objectives

The hypothalamic ventromedial nucleus (VMH) plays a major role in metabolic control, but the molecular mechanisms involved remain poorly defined. We analyzed the relevance of the BBSome, a protein complex composed of 8 Bardet-Biedl syndrome (BBS) proteins including BBS1, in VMH steroidogenic factor 1 (SF1) neurons for the control of energy homeostasis and related physiological processes.

Methods

We generated mice bearing selective BBSome disruption, through Bbs1 gene deletion, in SF1 neurons (SF1^Cre/Bbs1^fl/fl). We analyzed the consequence on body weight, glucose homeostasis, and cardiovascular autonomic function of BBSome loss in SF1 neurons.

Results

SF1^Cre/Bbs1^fl/fl mice had increased body weight and adiposity under normal chow conditions. Food intake, energy absorption, and digestive efficiency were not altered by Bbs1 gene deletion in SF1 neurons. SF1^Cre/Bbs1^fl/fl mice exhibited lower energy expenditure, particularly during the dark cycle. Consistent with this finding, SF1^Cre/Bbs1^fl/fl mice displayed reduced sympathetic nerve traffic and expression of markers of thermogenesis in brown adipose tissue. SF1^Cre/Bbs1^fl/fl mice also had lower sympathetic nerve activity to subcutaneous white adipose tissue that was associated with a protein expression profile that promotes lipid accumulation. Notably, despite obesity and hyperinsulinemia, SF1^Cre/Bbs1^fl/fl mice did not exhibit significant changes in glucose metabolism, insulin sensitivity, blood pressure, and baroreflex sensitivity.

Conclusions

Our findings demonstrate that the SF1 neuron BBSome is necessary for the regulation of energy homeostasis through modulation of the activity of the sympathetic nervous system and that the SF1 neuron BBSome is required for the development of obesity-related comorbidities.

SUBMITTER: Rouabhi M

PROVIDER: S-EPMC8065214 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Dynactin p150Glued, the largest subunit of the dynactin macromolecular complex, binds to both microtubules and tubulin dimers through the N-terminal cytoskeleton-associated protein and glycine-rich (CAP-Gly) and basic domains, and serves as an anti-catastrophe factor in stabilizing microtubules in neurons. P150Glued also initiates dynein-mediated axonal retrograde transport. Multiple missense mutations at the CAP-Gly domain of p150Glued are associated with motor neuron diseases and other neurodegenerative disorders, further supporting the importance of microtubule domains (MTBDs) in p150Glued functions. However, most functional studies were performed in vitro. Whether p150Glued is required for neuronal function and survival in vivo is unknown. METHODS:Using Cre-loxP genetic manipulation, we first generated a line of p150Glued knock-in mice by inserting two LoxP sites flanking the MTBD-coding exons 2 to 4 of p150Glued-encoding Dctn1 gene (Dctn1LoxP/), and then crossbred the resulting Dctn1LoxP/ mice with Thy1-Cre mice to generate the bigenic p150Glued (Dctn1LoxP/LoxP; Thy1-Cre) conditional knockout (cKO) mice for the downstream motor behavioral and neuropathological studies. RESULTS:P150Glued expression was completely abolished in Cre-expressing postnatal neurons, including corticospinal motor neurons (CSMNs) and spinal motor neurons (SMNs), while the MTBD-truncated forms remained. P150Glued ablation did not affect the formation of dynein/dynactin complex in neurons. The p150Glued cKO mice did not show any obvious developmental phenotypes, but exhibited impairments in motor coordination and rearing after 12 months of age. Around 20% loss of SMNs was found in the lumbar spinal cord of 18-month-old cKO mice, in company with increased gliosis, neuromuscular junction (NMJ) disintegration and muscle atrophy. By contrast, no obvious degeneration of CSMNs, striatal neurons, midbrain dopaminergic neurons, cerebellar granule cells or Purkinje cells was observed. Abnormal accumulation of acetylated ?-tubulin, and autophagosome/lysosome proteins was found in the SMNs of aged cKO mice. Additionally, the total and cell surface levels of glutamate receptors were also substantially elevated in the p150Glued-depleted spinal neurons, in correlation with increased vulnerability to excitotoxicity. CONCLUSION:Overall, our findings demonstrate that p150Glued is particularly required to maintain the function and survival of SMNs during aging. P150Glued may exert its protective function through regulating the transportation of autophagosomes, lysosomes, and postsynaptic glutamate receptors in neurons.