Objective: To assess the role of jejunum in insulin resistance in humans and in experimental animals. Design: Twenty-four subjects undergoing biliopancreatic diversion (BPD) or Roux-en-Y gastric bypass (RYGB) were enrolled. Insulin sensitivity was measured at baseline and at 1 week after surgery using oral glucose minimal model. We excluded the jejunum from intestinal continuity in pigs and created a jejunal loop with its vascular and nerve supply intact accessible from two cutaneous stomas, and reconnected the bowel with an end-to-end anastomosis. Glucose stable isotopes were given in the stomach or in the jejunal loop. In vitro studies using primary porcine and human hepatocytes or myoblasts tested the effects of plasma on gluconeogenesis or glucose uptake and insulin signalling. Results: Whole-body insulin sensitivity (S_I∙10⁴: 0.54±0.12 before vs 0.82±0.11 after BPD, p=0.024 and 0.41±0.09 before vs 0.65±0.09/pM/min after RYGB, p=not significant) and Glucose Disposition Index increased only after BPD. In pigs, insulin sensitivity was significantly lower when glucose was administered in the jejunal loop than in the stomach (glucose rate of disappearance (R_d) area under the curve (AUC)/insulin AUC∙10: 1.82±0.31 vs 2.96±0.33 mmol/pM/min, p=0.0017). Metabolomics showed a similar pattern before surgery and during jejunal-loop stimulation, pointing to a higher expression of gluconeogenetic substrates, a metabolic signature of impaired insulin sensitivity. A greater hepatocyte phosphoenolpyruvate-carboxykinase and glucose-6-phosphatase gene expression was elicited with plasma from porcine jejunal loop or before surgery compared with plasma from jejunectomy in pigs or jejunal bypass in humans. Stimulation of myoblasts with plasma from porcine jejunal loop or before surgery reduced glucose uptake, Ser473-Akt phosphorylation and GLUT4 expression compared with plasma obtained during gastric glucose administration after jejunectomy in pigs or after jejunal bypass in humans. Conclusion: Proximal gut plays a crucial role in controlling insulin sensitivity through a distinctive metabolic signature involving hepatic gluconeogenesis and muscle insulin resistance. Bypassing the jejunum is beneficial in terms of insulin-mediated glucose disposal in obesity. Trial registration number: NCT03111953.

Dodecanedioic acid (DC12) is a dicarboxylic acid present in protective polymers of fruit and leaves. We explored the effects of DC12 on metabolic dysfunction‐associated steatohepatitis (MASH) and obesity. DC12 supplementation (100 mg/kg/day) was added to a high‐fat diet (HFD) for 8 weeks in rodents to assess its impact on obesity and MASH prevention. Rats given DC12 experienced significant reductions of weight gain, liver and visceral fat weight, and improved glucose tolerance and insulin sensitivity. Liver histology showed protection against diet‐induced MASH, with reduced steatosis, hepatocyte ballooning, and fibrosis. For weight‐loss and MASH reversion, rats were fed HFD for 14 weeks, followed by 6 weeks with or without DC12. DC12 supplementation (100 mg/kg/day) led to a significant reduction of weight gain and liver weight. DC12 induced white adipose tissue beiging and reduced adiposity with a decrease of visceral fat. It also improved glucose tolerance, insulin sensitivity, and reduced hepatic gluconeogenic gene expression. Liver histology revealed a significant reduction in steatosis, hepatocyte ballooning, and inflammation as well as fibrosis, indicating MASH reversal. DC12 reduced hepatic lipogenesis enzymes as well as de novo lipogenesis measured by deuterated water and increased fatty acid β‐oxidation. Plasma lipid profile showed lower triglycerides and phosphatidylcholines in the DC12 group. Notably, DC12 decreased mINDY expression, the cell membrane Na+‐coupled citrate transporter, reducing citrate uptake and de‐novo lipogenesis, linking its effects to improved lipid metabolism and reduced steatosis. We found that during the hepatic first pass, half of the DC12 ingested with water was taken up by the liver. The concentration of DC12 in the portal vein falls within the range identified in vitro as sufficient to inhibit citrate transport in hepatocytes.

Body-mass index is a major determinant of left-ventricular-mass (LVM). Bariatric-metabolic surgery (BMS) reduces cardiovascular mortality. Its mechanism of action, however, often encompasses a weight-dependent effect. In this translational study, we aimed at investigating the mechanisms by which BMS leads to LVM reduction and functional improvement. Twenty patients (45.2 ± 8.5years) were studied with echocardiography at baseline and at 1,6,12 and 48 months after sleeve-gastrectomy (SG). Ten Wistar rats aged 10-weeks received high-fat diet ad libitum for 10 weeks before and 4 weeks after SG or sham-operation. An oral-glucose-tolerance-test was performed to measure whole-body insulin-sensitivity. Plasma metabolomics was analysed in both human and rodent samples. RNA quantitative Real-Time PCR and western blots were performed in rodent heart biopsies. The best-fitted partial-least-square discriminant-analysis model was used to explore the variable importance in the projection score of all metabolites. Echocardiographic LVM (-12%,-23%,-28% and -43% at 1,6,12 and 48 months, respectively) and epicardial fat decreased overtime after SG in humans while insulin-sensitivity improved. In rats, SG significantly reduced LVM and epicardial fat, enhanced ejection-fraction and improved insulin-sensitivity compared to sham-operation. Metabolomics showed a progressive decline of plasma branched-chain amino-acids (BCAA), alanine, lactate, 3-OH-butyrate, acetoacetate, creatine and creatinine levels in both humans and rodents. Hearts of SG rats had a more efficient BCAA, glucose and fatty-acid metabolism and insulin signaling than sham-operation. BCAAs in cardiomyocyte culture-medium stimulated lipogenic gene transcription and reduced mRNA levels of key mitochondrial β-oxidation enzymes promoting lipid droplet accumulation and glycolysis. After SG a prompt and sustained decrease of the LVM, epicardial fat and insulin resistance was found. Animal and in vitro studies showed that SG improves cardiac BCAA metabolism with consequent amelioration of fat oxidation and insulin signaling translating into decreased intra-myocytic fat accumulation and reduced lipotoxicity.

Over the past 40 years, the prevalence of obesity has risen dramatically, reaching epidemic proportions. Metabolic surgery has proven to be highly effective in treating obesity, leading to significant improvements or complete resolution of obesity-related comorbidities. Research conducted in both animals and humans suggests that the metabolic benefits achieved through metabolic surgery cannot be solely attributed to weight loss. Indeed, there has been an increasing recognition of intestinal inflammation as a novel factor influencing obesity. The gastrointestinal tract is continuously exposed to dietary components, particularly diets rich in saturated fats, which are known to contribute to obesity. It is now widely accepted that heat shock proteins can be released from various cells including intestinal epithelial cells and act as proinflammatory signals. Several studies have shown that circulating levels of glucose-regulated protein 78 (GRP78) are increased in subjects with obesity and correlate with the severity of the disease. Moreover, mice with a partial knockout of GRP78 are protected from diet-induced obesity. In this review, we discuss the role of GRP78 in the development of obesity. Several evidence suggests that GRP78 can influence adipogenesis, lipid droplets stabilization, insulin resistance, and liver steatosis. We also provide an update on GRP78 regulation following metabolic surgery, focusing on the bypass of the small intestine as a key factor for GRP78 secretion. Finally, we discuss the potential role of monoclonal antibodies against GRP78 as a treatment for obesity.

Background and Aims: Liver fibrosis is a major determinant of liver‐related events (LREs) in patients with metabolic dysfunction‐associated steatotic liver disease (MASLD). Effective stratification based on fibrosis severity is essential for accurate prognosis. The Enhanced Liver Fibrosis (ELF) test, a non‐invasive test measuring direct fibrosis markers, offers a potential alternative to traditional methods like FIB‐4, liver stiffness measurement (LSM) and liver biopsy. This study aims to evaluate the prognostic value of the ELF test in comparison with these established methods. Methods: We retrospectively analysed 289 MASLD patients (30.4% female, median age 49 years [IQR 39–58], 28% with type 2 diabetes) from the PROMETEO cohort (NCT04371042). We excluded patients with prior or current evidence of decompensated cirrhosis. At baseline, patients underwent liver biopsy, FIB‐4, ELF and LSM assessments. The primary outcome was development of Liver Related Events (LRE), a composite of liver‐related death, hepatocellular carcinoma, liver transplantation, ascites, encephalopathy or variceal bleeding. Results: Over a median follow‐up of 64 months [IQR 39–81], 41 patients (14.2%) experienced LREs. Event rates increased markedly across ELF categories (1% for ELF < 9.8, 27.8% for ELF ≥ 9.8 to < 11.3 and 72.7% for ELF ≥ 11.3). ELF demonstrated discriminative performance comparable to histological fibrosis stage and LSM, with the highest overall AUC among evaluated tests. In adjusted Cox models, higher ELF categories remained strongly associated with LRE risk, although confidence intervals were wide due to the limited number of events. Conclusions: In this biopsy‐proven MASLD cohort, ELF provided prognostic stratification for liver‐related events comparable to liver histology and LSM. Given the limited number of outcome events, these findings support the non‐inferiority of ELF rather than definitive superiority. Larger prospective studies are needed to confirm these results and refine risk prediction strategies.