Biology subjects

Benhamed, F.

Publications and source records attributed to Benhamed, F..

5 recordsLinked to original sources

bioRxiv2025

Hepatocyte FGF21 is not required for fasting-induced metabolic responses but guides protein appetite after energy depletion

Fasting initiates a coordinated metabolic response to preserve energy balance. As glycogen stores are depleted, the body transitions to mobilizing fatty acids from adipose tissue and generating ketone bodies in the liver to sustain the function of vital organs. A network of hormonal signals and transcriptional programs coordinate these adaptations. Among these, the hepatokine fibroblast growth factor 21 (FGF21) is strongly upregulated during fasting and has been proposed as a key mediator of the fasting response. To investigate the physiological functions of FGF21, we studied mice with hepatocyte-specific deletion of Fgf21. Although the liver is the primary source of circulating FGF21 during fasting, its absence in hepatocytes did not alter typical fasting-induced gene expression or key metabolic pathways such as hepatic gluconeogenesis, adipose tissue lipolysis, or ketone production. Instead, we uncovered a distinct role for FGF21 in promoting protein appetite following a fast. These findings challenge the conventional view of hepatocyte-produced FGF21 as a fasting-acting hormone and reveal a more specialized function in guiding nutrient selection after energy depletion.

physiology↗

bioRxiv2025

The gut insulin receptor acts as gatekeeper of intestinal barrier integrity

An impaired gut barrier has emerged as a potential driver of the low-grade inflammation that accompanies obesity and its complications. Among these, hyperglycemia per se has been proposed to sustain such increased intestinal permeability and subsequent translocation of bacterial endotoxins in the systemic circulation. Because reduced insulin signaling in the gut epithelium has also been reported upon obese conditions, we hypothesized that, beyond hyperglycemia, defective intestinal insulin signaling could directly compromise epithelial integrity. To mimic this diabesity feature, we induced deletion of the insulin receptor (IR) in the adult gut epithelium of IR{Delta}GUT mice. Remarkably, gut IR loss persistently maintained normal body weight and glucose homeostasis, thereby allowing the specific role of insulin action to be investigated. While IR{Delta}GUT mice exhibited increased intestinal paracellular permeability, mechanistic characterization of this gut leakiness revealed that IR{Delta}GUT mice displayed a rapid and drastic decline in Paneth cells anti-microbial defenses. This paralleled the onset of a cecal dysbiosis, as characterized by increased abundance of Pseudomonadota, and enhanced microbiota encroachment. Of note, IR{Delta}GUT mice exhibited intestinal stem cell (ISC) defects, as evidenced by reduced expression of ISC markers and ISC-mediated growth of intestinal organoids. Although expression of niche factors such as Wnt3a was diminished in Paneth cells isolated from IR{Delta}GUT mice, pharmacological activation of the canonical Wnt pathway failed to rescue the growth defects of IR-deleted gut organoids. The direct contribution of IR-downstream signaling to ISCs homeostasis was confirmed by the transcriptional reprogramming of FACS-sorted ISCs from IR{Delta}ISC mice. Finally, while gut IR loss did not worsen endotoxemia or impaired glycemic control upon HFD-feeding, IR{Delta}GUT displayed a higher susceptibility to chemically induced colitis and enteric infections (S. typhimurium, C. rodentium), underscoring intestinal insulin signaling as a key determinant of barrier integrity and epithelial homeostasis.

physiology↗

bioRxiv2024

Wnt/β-catenin signaling improves oxidative metabolism in skeletal muscle of obese ob/ob mice

BackgroundCanonical Wnt signaling is involved in many physiological and pathological states. As it regulates lipid metabolism and glucose homeostasis, its misregulation may lead to the development of diabetes and obesity. We have already reported that activation of the Wnt/{beta}-catenin canonical signaling pathway increased insulin sensitivity and prevented lipid deposits in rat skeletal muscle through a reciprocal regulation of Wnt10b and the lipogenic factor SREBP-1c. ResultsHere we have studied the role of Wnt/{beta}-catenin canonical signaling in skeletal muscle of genetically obese and diabetic (ob/ob) mice and their control ob/+ mice. We showed that Wnt10b and SREBP-1c expressions were conversely regulated in cultured mouse myoblasts isolated from lean ob/+ or obese ob/ob mice. Activation of the Wnt/{beta}-catenin pathway using Wnt10b overexpression or the selective GSK3 inhibitor 6-Bromo-indirubin-3oxime (BIO) was sufficient to decrease lipogenic genes expression in cultured myoblasts isolated from control and obese mice. In vivo, we performed direct electrotransfection of Wnt10b cDNA or BIO injections in Tibialis Anterior (TA) muscles of ob/ob and ob/+ mice. Both up-regulated Wnt10b gene expression and down-regulated SREBP-1c expression. Canonical Wnt signaling increased slow Myosin Heavy Chain-I (MHC-I) oxidative fiber number as well as fast Myosin Heavy Chain-IIA (MHC-IIA) oxidative fiber number, while decreasing fast glycolytic fiber number in TA muscle. In addition, Wnt signaling increased mitochondrial oxidative metabolism and respiratory reserve capacity by 2- and 3-fold in myotubes cultured from ob/ob and ob/+ mice muscles respectively. Surprisingly, the activation of the Wnt pathway was sufficient to reduce hyperglycemia by 30% within 3 weeks in ob/ob mice. ConclusionsOur results show that activation of Wnt/{beta}-catenin signaling in skeletal muscle induced a shift towards a more oxidative metabolism in myofibers, thus mimicking the effects of exercise training. Wnt10b could be a valuable candidate to develop therapeutic drugs for the treatment of obesity and/or type 2 diabetes.

cell biology↗

bioRxiv2021

Loss of intestinal ChREBP impairs absorption of dietary sugars and prevents glycemic excursion curves

Increased sugar consumption is a risk factor for features of the metabolic syndrome including obesity, hypertriglyceridemia, insulin resistance, diabetes, and nonalcoholic fatty liver disease. The gut epithelium, which plays a central role in dietary sugar digestion, absorption and metabolism has emerged a key actor of metabolic disorders. While the transcription factor ChREBP (Carbohydrate response element binding protein) has been established as a key player of the adaptive reprograming of cellular metabolism in various tissues upon glucose or fructose challenge, its specific contribution to the regulation of blood glucose upon dietary sugar intake was not previously addressed. We demonstrate here that ChREBP is abundantly expressed in the proximal gut epithelium, where carbohydrate digestion and absorption primarily occur and in particular L cells, which produce the glucoincretin GLP-1. The inducible deletion of ChREBP specifically in the mouse gut epithelium (Ch{Delta}GUT mice) resulted in the reduction of early glycemic excursion upon oral glucose load. Surprisingly, despite being associated with reduced GLP-1 production, loss of gut ChREBP activity significantly dampened glucose transepithelial flux, and thereby delayed glucose distribution to peripheral tissues. Among the underlying mechanisms, we unveil that Ch{Delta}GUT mice show an impaired expression of key intestinal hexose (glucose, galactose, fructose) transporters and metabolic enzymes as well as brush border dissacharidases. In agreement, intestinal ChREBP deficiency was accompanied by a precocious intolerance to both high-lactose and high-sucrose diets concomitant with mild galactose and severe fructose malabsorption syndromes. Altogether, our study demonstrates that, by transcriptionally orchestrating local digestion and absorption of dietary sugars, ChREBP activity in the mouse gut epithelium controls glucose appearance rate into systemic circulation and prevents against intolerance to mono- and disaccharides.

physiology↗

bioRxiv2021

Nuclear HMGB1 protects from non-alcoholic fatty liver diseases through negative regulation of liver X receptor

Dysregulations of lipid metabolism in the liver may trigger steatosis progression leading to potentially severe clinical consequences such as non-alcoholic fatty liver diseases (NAFLD). Molecular mechanisms underlying liver lipogenesis are very complex and fine-tuned by chromatin dynamics and the activity of multiple key transcription factors. Here, we demonstrate that the nuclear factor HMGB1 acts as a strong repressor of liver lipogenesis during metabolic stress in NAFLD. Mice with liver-specific Hmgb1-deficiency display exacerbated liver steatosis and hepatic insulin resistance when subjected to a high-fat diet or after fasting/refeeding. Global transcriptome and functional analysis revealed that the deletion of Hmgb1 gene enhances LXR activity resulting in increased lipogenesis. HMGB1 repression is not mediated through nucleosome landscape re-organization but rather via a preferential DNA occupation in region carrying genes regulated by LXR. Together these findings suggest that hepatocellular HMGB1 protects from liver steatosis development. HMGB1 may constitute a new attractive option to therapeutically target LXR axis during NAFLD.

pathology↗