Biology subjects

Langin, D.

Publications and source records attributed to Langin, D..

8 recordsLinked to original sources

bioRxiv2026

Identification of the Col4a3-/- mouse as a model of chronic kidney disease-associated cachexia

Background: Cachexia is a frequent complication of advanced chronic kidney disease (CKD), i.e. renal cachexia, particularly in patients undergoing hemodialysis in whom it represents one of the strongest predictors of morbidity and mortality. Yet, our understanding of the molecular mechanisms leading to body wasting in CKD and management of cachectic patients are still poorly defined. To date, a preclinical mouse model of robust and reproducible CKD-associated cachexia is missing. Here, we assessed in a systematic manner the cachectic phenotype of the genetic Col4a3-/- mouse model of CKD. Methods: 129/SvJ Col4a3-/- male and female animals were monitored longitudinally until they developed kidney failure. Measured glomerular filtration rate (mGFR), body composition and grip strength were recorded at baseline (6 weeks of age, before onset of kidney dysfunction) and at endpoint (CKD with weight loss or 12 weeks of age). The severity of CKD was confirmed by biochemical and histological analyses. Muscle atrophy was assessed via fiber cross-sectional area analysis, atrogene expression and transcriptomics. Adipose tissue wasting was assessed by measuring adipocyte area and proteins involved in lipid synthesis and breakdown. Liver acute phase response and systemic inflammation were evaluated by measuring circulating levels of key factors using ELISA. Results: Col4a3-/- animals developed CKD (decrease in mGFR: -85%, P<0.0001) and cachexia within 8-12 weeks of age. Cachexia was characterized by a progressive loss of body weight (-17.8% +/- 1.0, P<0.0001), lean (-8.2% +/- 2.0, P<0.0001) and fat mass (-66.5% +/- 4.7, P<0.0001) associated with reduced grip strength (-24.3% +/- 0.0, P=0.0002). At the tissue level, cachexia led to muscle atrophy and induction of atrogenes. Muscle transcriptomics further validated the cachectic phenotype of the Col4a3-/-, with 47% of genes altered in a similar manner with the well-established colon-C26 mouse model of cancer cachexia. It also revealed signatures that appeared more specific to renal cachexia. Adipose tissue wasting was characterized by a depletion in fat stores, consecutive to an imbalance between proteins involved in lipogenesis and lipolysis. Cachexia in this model was also associated with the induction of acute phase response in liver, elevated circulating levels of serum amyloid A and systemic inflammation, with the induction of established cachexia mediators (IL-6, GDF-15 P<0.0001). Both male and female mice developed cachexia. Conclusions: Our data highlight the potential of using the Col4a3-/- mouse model of CKD for the future study of renal cachexia, offering a more robust alternative to classically used models of partial nephrectomy or adenine-rich diet.

pathology↗

bioRxiv2026

Fatty acids from adipocyte lipolysis stimulate insulin secretion

White adipose tissue and pancreatic islets play central roles in the regulation of metabolic homeostasis. Although ectopic lipid accumulation is established as a driver of impaired insulin secretion, the acute contribution of adipocyte lipolysis to islet function remains poorly documented. Here, we investigated a mouse model with inducible adipocyte-specific deletion of both adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), which leads to defective adipocyte lipolysis. Despite preserved ex vivo islet function, these mice displayed a marked reduction in insulin secretion in response to stimulation of adipocyte {beta}3-adrenoceptors, as well as following glucose and arginine challenges. Mechanistically, we identified non-esterified fatty acids as critical mediators of lipolysis-driven insulin secretion, engaging pancreatic signaling of the free fatty acid receptors FFAR4 (a.k.a. GPR120) and FFAR1 (a.k.a. GPR40). The regulation of insulin secretion by adipocyte lipolysis was preserved in high-fat diet-induced obesity. These findings identify an underappreciated adipose-islet crosstalk that couples adipocyte lipolysis to insulin secretion and links lipid and glucose metabolism.

physiology↗

bioRxiv2025

Hepatocyte ERα orchestrates sex-specific liver adaptation to fasting and feeding states

Sex differences in hepatic physiology are thought to influence individual susceptibility to chronic liver diseases including Metabolic-Associated Steatotic Liver Disease (MALSD). Previous studies demonstrated the central contribution of estrogens which primarily influence liver biology through the activation of Estrogen Receptor alpha (ER). However, how ER signaling in hepatocyte modulates liver functions according to the nutritional status, a critical determinant of hepatic metabolism, remains to be characterized. The present study first reveals the nycthemeral expression profile of liver ER, which peaks during the feeding period (ZT16) in both male and female mice. ER expression is altered by reprogramming the hepatic circadian clock in response to inverted food intake, highlighting the influence of feeding on liver ER expression patterns. As ER is mainly expressed in hepatocytes both in human and mouse livers, the functional role of hepatocyte ER during fasting or feeding state was then delineated, using mice harboring ER hepatocyte-specific deletion (ERhep-/-) compared with their wild-type littermates (ERhep+/+). Transcriptomic analyses reveal significant sex differences in the adaptation of liver functions to this contrasted nutritional status, as well as the sex-specific regulatory effects of hepatocyte ER. In such physiological settings, hepatocyte ER deletion does not influence liver transcriptomic profiles in males but significantly alters gene expression in female livers, both fed and fasted conditions. Hepatocyte ER more specifically controls genes associated with inflammatory responses and fatty acid metabolic pathways in females, modulating the ChREBP and PPAR pathways in feeding or fasting states, respectively. Thus, hepatocyte ER is integral to liver metabolic adaptations to fasting and feeding in females but not in males, thus exhibiting both sex-specific and diet-dependent actions. Further characterizing sex differences in liver metabolic flexibility, these results provide new information to develop sex-based strategies for the prevention and management of MASLD.

physiology↗

bioRxiv2025

Chain length defines the spatial segregation and metabolic fate of fatty acids in adipocytes

Adipocytes primarily store fatty acids (FAs) as triacylglycerols (TGs) within lipid droplets, releasing them through lipolysis to meet systemic energy demands. While the metabolism of long-chain fatty acids (LCFAs) in adipocytes has been extensively characterized, it remains ill-defined how adipocytes utilize fatty acids depending on chain length and structure. Our work demonstrates that short- and medium-chain fatty acids (SMCFAs) are esterified into TGs within lipid droplets, rather than being incorporated into other FA-containing lipid species. During lipolytic activation, TGs enriched in SMCFAs are hydrolysed more rapidly than those containing LCFAs. This accelerated mobilization is facilitated by the preferential localization of SMCFA-containing TGs at the lipid droplet surface, which enhances accessibility to adipose triglyceride lipase. Unlike LCFAs, which are efficiently released for utilization by peripheral tissues, SMCFAs are predominantly oxidized within adipocytes. These findings reveal a unique metabolic routing of SMCFAs, indicating their preferential intracellular oxidation to support adipocyte energy requirements.

biochemistry↗

bioRxiv2024

Effect of thermoneutral housing on MASLD severity, hepatic gene expression, and BAT activation during beta3-adrenergic stimulation in mice

Metabolic dysfunction-associated steatotic liver disease (MASLD), and its more advanced stage metabolic dysfunction-associated steatohepatitis, is the most common chronic liver disease, constituting a major public health issue. No medication is approved for MASLD treatment, and relevant preclinical models are needed to define molecular mechanisms underlying MASLD pathogenesis, and evaluate therapeutic approaches. Here we demonstrated that compared to standard temperature housing, thermoneutral housing aggravated western diet (WD)-induced obesity, diabetes, and steatosis in male mice, which was associated with increased hepatic expression of inflammation- and fibrosis-related genes. Accordingly, compared to standard-housed mice, thermoneutral-housed WD-fed mice developed more severe hepatic inflammation and fibrosis. The liver is the central metabolic organ in whole-body metabolic homeostasis. We used thermoneutrally housed mice with WD-induced MASLD to examine the effect of MASLD during {beta}3- adrenergic stimulation, and found that diet-induced MASLD was associated with defective inter- organ metabolic cross-talk, leading to impaired brown adipose tissue activation. HighlightsO_LIThermoneutral housing promotes WD-induced obesity and MASLD in mice C_LIO_LIThermoneutral housing fosters WD-induced change in gene expression C_LIO_LIThermoneutral housing fosters hepatic inflammation and fibrosis C_LIO_LIMASLD is associated with defective BAT response to {beta}3-adrenergic stimulation C_LI

physiology↗

bioRxiv2021

ATGL-dependent white adipose tissue lipolysis controls hepatocyte PPARα activity

ObjectiveIn hepatocytes, peroxisome proliferator-activated receptor (PPAR) acts as a lipid sensor that regulates hepatic lipid catabolism during fasting and orchestrates a genomic response required for whole-body homeostasis. This includes the biosynthesis of ketone bodies and the secretion of the starvation hormone fibroblast growth factor 21 (FGF21). Several lines of evidence suggest that adipose tissue lipolysis contributes to this specific process. However, whether adipose tissue lipolysis is a dominant signal for the extensive remodeling of liver gene expression dependent on PPAR has not been investigated. MethodsFirst, using mice lacking adipose tissue lipolysis through adipocyte-specific deletion of adipose triglyceride lipase (ATGL), we characterized the responses dependent on adipocyte ATGL during fasting. Next, we performed liver whole genome expression analysis in fasted mice upon deletion of adipocyte ATGL or hepatocyte PPAR. Finally, we tested the consequences of hepatocyte-specific PPAR deficiency during pharmacological induction of adipocyte lipolysis with a {beta}3-adrenergic receptor agonist. ResultsIn the absence of ATGL in adipocytes, ketone body and FGF21 productions were impaired in response to starvation. Liver transcriptome analysis revealed that adipocyte ATGL is critical for regulation of hepatic gene expression during fasting and highlighted a strong enrichment in PPAR target genes in this condition. Genome expression analysis confirmed that a large set of fasting-induced genes are sensitive to both ATGL and PPAR. Adipose tissue lipolysis induced by acute activation of the {beta}3-adrenergic receptor also triggered PPAR-dependent responses in the liver, supporting a role for adipocyte-derived fatty acids as dominant signals for hepatocyte PPAR activity. In addition, the absence of hepatocyte PPAR altered brown adipose tissue (BAT) morphology and reduced UCP1 expression upon stimulation of the {beta}3-adrenergic receptor. In agreement with this finding, mice lacking hepatocyte PPAR showed decreased tolerance to acute cold exposure. ConclusionsThese results underscore the central role of hepatocyte PPAR in the sensing of adipocyte-derived fatty acids and reveal that its activity is essential for full activation of BAT. Intact PPAR activity in hepatocytes is required for cross-talk between adipose tissues and the liver during fat mobilization during fasting and cold exposure.

physiology↗

bioRxiv2019

Atrial natriuretic peptide orchestrates a coordinated physiological response to fuel non shivering thermogenesis

Atrial natriuretic peptide (ANP) is a cardiac hormone controlling blood volume and arterial pressure in mammals. It is unclear whether and how ANP controls cold-induced thermogenesis in vivo. Here we show that acute cold exposure induces cardiac ANP secretion in mice and humans. Genetic inactivation of ANP promotes cold intolerance and suppresses about half of cold-induced brown adipose tissue (BAT) activation in mice. While white adipocytes are resistant to ANP-mediated lipolysis at thermoneutral temperature in mice, cold exposure renders white adipocytes fully responsive to ANP to activate lipolysis and a thermogenic program, a physiological response which is dramatically suppressed in ANP null mice. ANP deficiency also blunts liver triglycerides and glycogen metabolism thus impairing fuel availability for BAT thermogenesis. ANP directly increases mitochondrial uncoupling and thermogenic genes expression in human white and brown adipocytes. Together, these results indicate that ANP is a major physiological trigger of BAT thermogenesis upon cold exposure in mammals.

physiology↗

bioRxiv2018

Hepatocyte-specific deletion of Pparα promotes NASH in the context of obesity

ObjectivesPeroxisome proliferator activated receptor (PPAR) acts as a fatty acid sensor to orchestrate the transcription of genes coding for rate-limiting enzymes required for lipid oxidation in hepatocytes. Mice only lacking Ppar in hepatocytes spontaneously develop steatosis without obesity in aging. Altough steatosis is a benign condition it can develop into non alcoholic steatohepatitis (NASH), which may progress to irreversible damage, such as fibrosis and hepatocarcinoma. While NASH appears as a major public health concern worldwide, it remains an unmet medical need. Several drugs are being tested in clinical trials, including pharmacological agonists for the different PPAR isotypes. In current study, we investigated the role of hepatocyte PPAR in a preclinical model of steatosis.\n\nMethods/ResultsWe have investigated the role of hepatocyte PPAR in a preclinical model of steatosis using High Fat Diet (HFD) feeding as a model of obesity in C57BL/6J male Wild-Type mice (WT), in whole-body (Ppar-/-) mice and in mice lacking Ppar in hepatocyte (Pparhep-/-). We provide evidence that Ppar deletion in hepatocytes promotes NASH in mice fed an HFD. This enhanced NASH susceptibility occurs without development of glucose intolerance. Moreover, our data reveal that non-hepatocytic PPAR activity predominantly contributes to the metabolic response to HFD.\n\nConclusionTaken together, our data support hepatocyte PPAR as being essential to the prevention of steatosis progression to NASH and that extra-hepatocyte PPAR activity contributes to whole-body lipid homeostasis.\n\nHighlightsO_LIPpar deletion in hepatocytes promotes steatosis and inflammation in HFD-induced obesity\nC_LIO_LIHepatocyte-specific deletion of Ppar dissociates NAFLD from glucose intolerance in HFD-induced obesity obesity\nC_LIO_LIExtrahepatic PPAR activity contributes to the metabolic response to HFD-induced obesity\nC_LI

pathology↗