Biology subjects

Rocher, A.

Publications and source records attributed to Rocher, A..

3 recordsLinked to original sources

bioRxiv2023

Ablation of carotid body activity reverses diabesity by improving white and brown adipose tissue sympathetic innervation and metabolism

Finding novel pathological mechanisms that lead to innovative strategies to treat obesity and its associated illness are critically needed. The carotid bodies (CB) are metabolic sensors whose dysfunction contributes to insulin resistance and glucose intolerance development. Herein, we find that the ablation of CB activity, through resection of carotid sinus nerve (CSN) promotes weight loss and restores metabolic function in high fat (HF) rodents, by increasing WAT basal metabolism and by restoring WAT and BAT sympathetic activation. Moreover, we found that CSN resection rescues adipose tissue sympathetic/catecholamine resistance present in obesity states. Additionally, we found that the CB signals integrated in the paraventricular nucleus of the hypothalamus are decreased in obesity states and that CSN denervation in HF animals restore neuronal activity in this region. By inducing energy expenditure via the increase in WAT and BAT metabolism, CB modulation might be used as a therapeutic target for obesity and dysmetabolism. HighlightsO_LIAblation of carotid body (CB) activity promotes weight loss C_LIO_LICarotid body modulates white and brown adipose tissue metabolism C_LIO_LIAblation of CB activity rescues adipose tissue sympathetic resistance in obesity C_LIO_LICarotid sinus nerve resection restored the altered neuronal activity induced by obesity in the paraventricular nucleus of the hypothalamus C_LI

physiology↗

bioRxiv2023

Chronic intermittent hypoxia induced-dysmetabolism is associated with hepatic oxidative stress, mitochondrial dysfunction and inflammation

The association between obstructive sleep apnea (OSA) and metabolic disorders is well-established but the underlying mechanisms that elucidate this relationship remain incompletely understood. Since the liver is a major organ in the maintenance of metabolic homeostasis, we hypothesize that liver dysfunction plays a crucial role in the pathogenesis of metabolic dysfunction associated with obstructive sleep apnea (OSA). Herein, we explored the underlying mechanisms of this association within the liver. Experiments were performed in male Wistar rats fed with a control or high fat (HF) diet (60% lipid-rich) for 12 weeks. Half of the groups were exposed to chronic intermittent hypoxia (CIH) (30 hypoxic (5% O2) cycles, 8 h/day) that mimics OSA, in the last 15 days. Insulin sensitivity and glucose tolerance were assessed. Liver samples were collected for evaluation of lipid deposition, insulin signaling, glucose homeostasis, hypoxia, oxidative stress, antioxidant defenses, mitochondrial biogenesis and inflammation. Both CIH and HF diet induced dysmetabolism, a state not aggravated in animals submitted to HF plus CIH. CIH aggravates hepatic lipid deposition in obese animals. Hypoxia-inducible factors levels were altered by these stimuli. CIH decreased the levels of oxidative phosphorylation complexes in both groups and the levels of SOD-1. HF diet reduced mitochondrial density and hepatic antioxidant capacity. CIH and HF diet produced alterations in cysteine-related thiols and pro-inflammatory markers. The results obtained suggest that hepatic mitochondrial dysfunction and oxidative stress, leading to inflammation, may be significant factors contributing to the development of dysmetabolism associated with OSA.

physiology↗

bioRxiv2022

CARD9 in Neutrophils Protects from Colitis and Controls Mitochondrial Metabolism and Cell Survival

ObjectivesInflammatory bowel disease (IBD) results from a combination of genetic predisposition, dysbiosis of the gut microbiota and environmental factors, leading to alterations in the gastrointestinal immune response and chronic inflammation. Caspase recruitment domain 9 (Card9), one of the IBD susceptibility genes, has been shown to protect against intestinal inflammation and fungal infection. However, the cell types and mechanisms involved in the CARD9 protective role against inflammation remain unknown. DesignWe used dextran sulfate sodium (DSS)-induced and adoptive transfer colitis models in total and conditional CARD9 knock-out mice to uncover which cell types play a role in the CARD9 protective phenotype. The impact of Card9 deletion on neutrophil function was assessed by an in vivo model of fungal infection and various functional assays, including endpoint dilution assay, apoptosis assay by flow cytometry, proteomics and real time bioenergetic profile analysis (Seahorse). ResultsLymphocytes are not intrinsically involved in the CARD9 protective role against colitis. CARD9 expression in neutrophils, but not in epithelial or CD11c+ cells, protects against DSS-induced colitis. In the absence of CARD9, mitochondrial dysfunction in neutrophils leads to their premature death through apoptosis, especially in oxidative environment. The decrease of fonctional neutrophils in tissues could explain the impaired containment of fungi and increased susceptibility to intestinal inflammation. ConclusionThese results provide new insight into the role of CARD9 in neutrophil mitochondrial function and its involvement in intestinal inflammation, paving the way for new therapeutic strategies targeting neutrophils. Summary boxO_LIWhat is already known about this subject? O_LIInflammatory bowel disease (IBD) results from genetic predisposition, microbiota dysbiosis and environmental factors, but the alterations of the immune response leading to chronic intestinal inflammation are still not fully understood. C_LIO_LICaspase recruitment domain 9 (Card9), one of the IBD susceptibility genes, has been shown to protect against intestinal inflammation and fungal infection. C_LIO_LIHowever, the cell types and cellular mechanisms involved in the CARD9 protective role against inflammation remain unknown. C_LI C_LIO_LIWhat are the new findings? O_LICARD9 expression in neutrophils, but not in lymphocytes, epithelial cells or CD11c+ cells, protects against DSS-induced colitis. C_LIO_LIIn the absence of CARD9, mitochondrial dysfunction in neutrophils leads to their premature death through apoptosis, especially in oxidative environment. C_LIO_LIThe decrease of fonctional neutrophils in tissues could explain the impaired containment of fungi and increased susceptibility to intestinal inflammation. C_LI C_LIO_LIHow might it impact on clinical practice in the foreseeable future? O_LIThese results provide new insight into the role of CARD9 in neutrophil mitochondrial function and its involvement in intestinal inflammation. C_LIO_LIUnderstanding the role of neutrophils in chronic inflammation could lead to innovative therapeutic strategies targeting these key immune cells for various complex diseases. C_LI C_LI

immunology↗