Nutrition & Metabolism[JOURNAL]
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200 papers
Upper small intestine microbiome in obesity and related metabolic disorders: A new field of investigation.
Steinbach E, Masi D, Ribeiro A … +3 more , Serradas P, Le Roy T, Clément K
Metabolism · 2024 Jan · PMID 37884078 · Publisher ↗
The study of the gut microbiome holds great promise for understanding and treating metabolic diseases, as its functions and derived metabolites can influence the metabolic status of the host. While research on the fecal...
The study of the gut microbiome holds great promise for understanding and treating metabolic diseases, as its functions and derived metabolites can influence the metabolic status of the host. While research on the fecal microbiome has provided valuable insights, it tells us only part of the story. This limitation arises from the substantial variations in microorganism distribution throughout the gastrointestinal tract due to changes in physicochemical conditions. Thus, relying solely on the fecal microbiome may not be sufficient to draw comprehensive conclusions about metabolic diseases. The proximal part of the small intestine, particularly the jejunum, indeed, serves as the crucial site for digestion and absorption of nutrients, suggesting a potential role of its microbiome in metabolic regulation. Unfortunately, it remains relatively underexplored due to limited accessibility. This review presents current evidence regarding the relationships between the microbiome in the upper small intestine and various phenotypes, focusing on obesity and type 2 diabetes, in both humans and rodents. Research on humans is still limited with variability in the population and methods used. Accordingly, to better understand the role of the whole gut microbiome in metabolic diseases, studies exploring the human microbiome in different niches are needed.
Dopamine in the nucleus accumbens shell controls systemic glucose metabolism via the lateral hypothalamus and hepatic vagal innervation in rodents.
Diepenbroek C, Rijnsburger M, van Irsen AAS … +16 more , Eggels L, Kisner A, Foppen E, Unmehopa UA, Berland C, Dólleman S, Hardonk M, Cruciani-Guglielmacci C, Faust RP, Wenning R, Maya-Monteiro CM, Kalsbeek A, Aponte Y, Luquet S, Serlie MJM, la Fleur SE
Metabolism · 2024 Jan · PMID 37804881 · Publisher ↗
BACKGROUND: Growing evidence demonstrates the role of the striatal dopamine system in the regulation of glucose metabolism. Treatment with dopamine antagonists is associated with insulin resistance and hyperglycemia, whi...
BACKGROUND: Growing evidence demonstrates the role of the striatal dopamine system in the regulation of glucose metabolism. Treatment with dopamine antagonists is associated with insulin resistance and hyperglycemia, while dopamine agonists are used in treatment of type 2 diabetes. The mechanism underlying striatal dopamine effects in glucose metabolism, however is not fully understood. Here, we provide mechanistic insights into the role of nucleus accumbens shell (sNAc) dopaminergic signaling in systemic glucose metabolism. METHODS: Endogenous glucose production (EGP), blood glucose and mRNA expression in the lateral hypothalamic area (LHA) in male Wistar rats were measured following infusion of vanoxerine (VNX, dopamine reuptake inhibitor) in the sNAc. Thereafter, we analyzed projections from sNAc Drd1-expressing neurons to LHA using D1-Cre male Long-Evans rats, Cre-dependent viral tracers and fluorescence immunohistochemistry. Brain slice electrophysiology in adult mice was used to study spontaneous excitatory postsynaptic currents of sNAc Drd1-expressing neurons following VNX application. Finally, we assessed whether GABAergic LHA activity and hepatic vagal innervation were required for the effect of sNAc-VNX on glucose metabolism by combining infusion of sNAc-VNX with LHA-bicuculline, performing vagal recordings and combining infusion of sNAc-VNX with hepatic vagal denervation. RESULTS: VNX infusion in the sNAc strongly decreased endogenous glucose production, prevented glucose increases over time, reduced Slc17A6 and Hcrt mRNA in LHA, and increased vagal activity. Furthermore, sNAc Drd1-expressing neurons increased spontaneous firing following VNX application, and viral tracing of sNAc Drd1-expressing neurons revealed direct projections to LHA with on average 67 % of orexin cells directly targeted by sNAc Drd1-expressing neurons. Importantly, the sNAc-VNX-induced effect on glucose metabolism was dependent on GABAergic signaling in the LHA and on intact hepatic vagal innervation. CONCLUSIONS: We show that sNAc dopaminergic signaling modulates hepatic glucose metabolism through GABAergic inputs to glutamatergic LHA cells and hepatic vagal innervation. This demonstrates that striatal control of glucose metabolism involves a dopaminergic sNAc-LHA-liver axis and provides a potential explanation for the effects of dopamine agonists and antagonists on glucose metabolism.
Pharmacotherapy before and after bariatric surgery.
Alabduljabbar K, le Roux CW
Metabolism · 2023 Nov · PMID 37730085 · Publisher ↗
Diabetes is a chronic disease that affects a vast number of individuals globally, and without optimal treatment, can lead to significant health complications. Moreover, obesity is another chronic disease with several com...
Diabetes is a chronic disease that affects a vast number of individuals globally, and without optimal treatment, can lead to significant health complications. Moreover, obesity is another chronic disease with several complications, which includes type 2 diabetes. Bariatric surgery is a viable long-term choice for managing diseases such as obesity and type 2 diabetes. However, the impact of pharmacotherapy before and after surgery remains unclear. In this review, we assessed the use of pharmacotherapy in patients with obesity with or without diabetes before and after bariatric surgery, focusing on weight loss, glycemic control, and the risk of postoperative complications. We showed that anti-obesity medication has become increasingly important in managing obesity and type 2 diabetes, both before and after bariatric surgery. The use of preoperative pharmacotherapy can optimize patients for surgery and reduce perioperative complications. Meanwhile, postoperative pharmacotherapy can maximize weight loss, improve metabolic outcomes, and lower the risk of weight regain. Medications such as sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, and combination therapies, are now very effective for treating obesity and type 2 diabetes mellitus. However, optimal timing, duration, and which combinations of pharmacotherapy to use with bariatric surgery remain unclear. Additionally, the long-term safety and efficacy of these treatments should be assessed. Integrating pharmacotherapy with bariatric surgery is a promising approach to managing obesity and type 2 diabetes, providing patients with additional options for achieving sustainable weight loss and improving their metabolic health.
Milestones in the journey towards addressing obesity; Past trials and triumphs, recent breakthroughs, and an exciting future in the era of emerging effective medical therapies and integration of effective medical therapies with metabolic surgery.
Kokkorakis M, Katsarou A, Katsiki N … +1 more , Mantzoros CS
Metabolism · 2023 Nov · PMID 37689110 · Publisher ↗
The 21st century is characterized by an increasing incidence and prevalence of obesity and the burden of its associated comorbidities, especially cardiometabolic diseases, which are reaching pandemic proportions. In the...
The 21st century is characterized by an increasing incidence and prevalence of obesity and the burden of its associated comorbidities, especially cardiometabolic diseases, which are reaching pandemic proportions. In the late '90s, the "black box" of adipose tissue and energy homeostasis was opened with the discovery of leptin, transforming the adipose tissue from an "inert fat-storage organ" to the largest human endocrine organ and creating the basis on which more intensified research efforts to elucidate the pathogenesis of obesity and develop novel treatments were based upon. Even though leptin was eventually not proven to be the "standalone magic bullet" for the treatment of common/polygenic obesity, it has been successful in the treatment of monogenic obesity syndromes. Additionally, it shifted the paradigm of treating obesity from a condition due to "lack of willpower" to a disease due to distinct underlying biological mechanisms for which specific pharmacotherapies would be needed in addition to lifestyle modification. Subsequently, the melanocortin pathway proved to be an equally valuable pathway for the pharmacotherapy of obesity. Melanocortin receptor agonists have recently been approved for treating certain types of syndromic obesity. Other molecules- such as incretins, implicated in energy and glucose homeostasis- are secreted by the gastrointestinal tract. Glucagon-like peptide 1 (GLP-1) is the most prominent one, with GLP-1 analogs approved for common/polygenic obesity. Unimolecular combinations with other incretins, e.g., GLP-1 with gastric inhibitory polypeptide and/or glucagon, are expected to be approved soon as more effective pharmacotherapies for obesity and its comorbidities. Unimolecular combinations with other compounds and small molecules activating the receptors of these molecules are currently under investigation as promising future pharmacotherapies. Moreover, metabolic and bariatric surgery has also demonstrated impressive results, especially in the case of morbid obesity. Consequently, this broadening therapeutic armamentarium calls for a well-thought-after and well-coordinated multidisciplinary approach, for instance, through cardiometabolic expertise centers, that would ideally address effectively and cost-effectively obesity and its comorbidities, providing tangible benefits to large segments of the population.
Additive impact of diabetes and sarcopenia on all-cause and cardiovascular mortality: A longitudinal nationwide population-based study.
Song E, Hwang SY, Park MJ … +10 more , Jang A, Kim KJ, Yu JH, Kim NH, Yoo HJ, Seo JA, Kim SG, Kim NH, Baik SH, Choi KM
Metabolism · 2023 Nov · PMID 37611822 · Publisher ↗
OBJECTIVE: Diabetes mellitus (DM) and sarcopenia (SP) are growing public health concerns in an aging society, which share common pathophysiological mechanisms and are associated with serious health consequences. We inves...
OBJECTIVE: Diabetes mellitus (DM) and sarcopenia (SP) are growing public health concerns in an aging society, which share common pathophysiological mechanisms and are associated with serious health consequences. We investigated the impact of DM and SP on all-cause and cardiovascular mortalities in a longitudinal nationwide population-based study. METHODS: The study analyzed data from the Korea National Health and Nutrition Examination Survey conducted between 2008 and 2011, including information on appendicular skeletal muscle mass data. Mortality data up to December 2020 were retrieved from the National Death Registry. RESULTS: Among the 17,920 participants, 14,737 (82.2 %) had neither DM nor SP (DM-/SP-), 1349 (7.5 %) had only DM (DM+/SP-), 1425 (8.0 %) had only SP (DM-/SP+), and 409 (2.3 %) had both DM and SP (DM+/SP+). Compared to the DM-/SP- group, the DM-/SP+ and DM+/SP+ groups demonstrated increased all-cause mortality with adjusted hazard ratios (HRs) of 1.47 (95 % confidence interval [CI]: 1.14-1.89) and 1.85 (95 % CI: 1.28-2.69), respectively, while the DM+/SP- group did not (HR 1.29, 95 % CI: 0.97-1.74). The DM+/SP+ group demonstrated the highest risk of overall mortality (p-for-trend <0.001). Compared to the DM-/SP- group, only the DM+/SP+ group demonstrated increased cardiovascular mortality with HRs of 2.10 (95 % CI: 1.11-4.00) while the DM+/SP- (HR 1.35, 95 % CI: 0.79-2.30) and DM-/SP+ (HR 1.42, 95 % CI: 0.84-2.43) groups did not. CONCLUSIONS: The coexistence of DM and SP additively increased the risk of all-cause and cardiovascular mortality. Individuals with either disease may require more careful management to prevent the development of the other disease to reduce mortality.
From non-alcoholic fatty liver disease (NAFLD) to steatotic liver disease (SLD): an ongoing journey towards refining the terminology for this prevalent metabolic condition and unmet clinical need.
Kokkorakis M, Boutari C, Katsiki N … +1 more , Mantzoros CS
Metabolism · 2023 Oct · PMID 37517792 · Publisher ↗
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Uroguanylin prevents hepatic steatosis, mitochondrial dysfunction and fibrosis in obesity-associated NAFLD.
Fernández-Sáez EM, Losarcos M, Becerril S … +12 more , Valentí V, Moncada R, Martín M, Burrell MA, Catalán V, Gómez-Ambrosi J, Mugueta C, Colina I, Silva C, Escalada J, Frühbeck G, Rodríguez A
Metabolism · 2023 Oct · PMID 37517791 · Publisher ↗
BACKGROUND: The biological mediators supporting the resolution of liver steatosis, inflammation and fibrosis after bariatric surgery in patients with obesity and NAFLD remain unclear. We sought to analyze whether uroguan...
BACKGROUND: The biological mediators supporting the resolution of liver steatosis, inflammation and fibrosis after bariatric surgery in patients with obesity and NAFLD remain unclear. We sought to analyze whether uroguanylin and guanylin, two gut hormones involved in the regulation of satiety, food preference and adiposity, are involved in the amelioration of obesity-associated NAFLD after bariatric surgery. METHODS: Proguanylin (GUCA2A) and prouroguanylin (GUCA2B) were measured in 214 participants undergoing bariatric surgery with biopsy-proven NAFLD diagnosis. Pathways involved in lipid metabolism, mitochondrial network and fibrogenesis were evaluated in liver biopsies (n = 137). The effect of guanylin and uroguanylin on these metabolic functions was assessed in HepG2 hepatocytes and LX-2 hepatic stellate cells (HSC) under lipotoxic and profibrogenic conditions. RESULTS: Plasma and hepatic expression of GUCA2B were decreased in obesity-associated NAFLD. Both GUCA2A and GUCA2B levels were increased after sleeve gastrectomy and Roux-en-Y gastric bypass in parallel to the improved liver function. The liver of patients with type 2 diabetes showed impaired mitochondrial β-oxidation, biogenesis, dynamics as well as increased fibrosis. Uroguanylin diminished the lipotoxicity in palmitate-treated HepG2 hepatocytes, evidenced by decresased steatosis and lipogenic factors, as well as increased mitochondrial network expression, AMPK-induced β-oxidation and oxygen consumption rate. Additionally, uroguanylin, but not guanylin, reversed HSC myofibroblast transdifferentiation as well as fibrogenesis after TGF-β1 stimulation. CONCLUSIONS: Uroguanylin constitutes a protective factor against lipotoxicity, mitochondrial dysfunction and fibrosis. Increased GUCA2B levels might contribute to improve liver injury in patients with obesity-associated NAFLD after bariatric surgery.
Ferroptosis, a new pathogenetic mechanism in cardiometabolic diseases and cancer: Is there a role for statin therapy?
Sahebkar A, Foroutan Z, Katsiki N … +2 more , Jamialahmadi T, Mantzoros CS
Metabolism · 2023 Sep · PMID 37442270 · Publisher ↗
One of the newly recognized types of cell death is ferroptosis which is related to the accumulation of iron and lipid-reactive oxygen species. Ferroptosis is considered a programmed cell death with a different mechanism...
One of the newly recognized types of cell death is ferroptosis which is related to the accumulation of iron and lipid-reactive oxygen species. Ferroptosis is considered a programmed cell death with a different mechanism from apoptosis, necrosis, and autophagy. Emerging evidence suggests that ferroptosis may occur in the context of cardiovascular disease (CVD), cancer, neurodegenerative diseases, and non-alcoholic fatty liver disease (NAFLD). Statins are the first-line therapy for dyslipidemia. The suppression of the HMG-CoA reductase by statins leads to decreased expression of glutathione peroxidase 4 (GPX4), a key regulator of lipid peroxidation, which in turn results in lipid ROS production and induction of ferroptosis. Experimental data suggest that statins may act as anti-cancer drugs by enhancing tumor cells' ferroptosis. In contrast, statins have also been reported to mitigate ferroptosis in animal models of myocardial ischemia-reperfusion and heart failure. This mini-review presents statin effects on the ferroptosis pathway, based on up-to-date in vivo and in vitro research. Furthermore, the potential impact of these effects on cardiometabolic diseases (e.g., CVD and NAFLD) and cancer is briefly discussed. Overall, there is a need for future studies focusing on statin-induced changes in ferroptosis as a therapeutic approach to such diseases.
Nonalcoholic fatty liver disease (NAFLD) and associated mortality in individuals with type 2 diabetes, pre-diabetes, metabolically unhealthy, and metabolically healthy individuals in the United States.
Golabi P, Paik JM, Kumar A … +5 more , Al Shabeeb R, Eberly KE, Cusi K, GunduRao N, Younossi ZM
Metabolism · 2023 Sep · PMID 37380016 · Publisher ↗
BACKGROUND: The prevalence of nonalcoholic fatty liver disease (NAFLD) is high among subjects with type 2 diabetes (T2D). However, the prevalence and outcomes of NAFLD among individuals with pre-diabetes (PreD) and metab...
BACKGROUND: The prevalence of nonalcoholic fatty liver disease (NAFLD) is high among subjects with type 2 diabetes (T2D). However, the prevalence and outcomes of NAFLD among individuals with pre-diabetes (PreD) and metabolically healthy and metabolically unhealthy individuals without T2D are not known. Our aim was to assess prevalence and mortality of NAFLD among these four groups. METHODS: The Third National Health and Nutrition Examination Survey (NHANES) III (1988-1994) with mortality data (follow up to 2019) via linkage to the National Death Index was utilized. NAFLD was defined by ultrasound and absence of other liver diseases and excess alcohol use. Pre-D was defined as fasting plasma glucose values of 100-125 mg/dL and/or HbA1c level between 5.7 %-6.4 % in the absence of established diagnosis of T2D. Metabolically healthy (MH) was defined if all of the following criteria were absent: waist circumference of ≥102 cm (men) or ≥ 88 cm (women) or BMI of ≥30; blood pressure (BP) ≥ 130/85 mmHg or using BP-lowering medication; triglyceride level ≥ 150 mg/dL or using lipid-lowering medication; lipoprotein cholesterol level of <40 mg/dL (men) or < 50 mg/dL (women); homeostasis model assessment of insulin resistance (HOMA-IR) score ≥ 2.5; C-reactive protein (CRP) level of >2 mg/L; Pre-D and T2D. Metabolically unhealthy (MU) individuals were defined as the presence of any component of metabolic syndrome but not having Pre-D and T2D. Competing risk analyses of cause-specific mortality were performed. FINDINGS: 11,231 adults (20-74y) were included: mean age 43.4 years; 43.9 % male; 75.4 % white, 10.8 % Black, and 5.4 % Mexican American, 18.9 % NAFLD, 7.8 % T2D; 24.7 % PreD; 44.3 % MU; and 23.3 % in MH individuals. In multivariable adjusted logistic model, as compared to MH individuals, the highest risk of having NAFLD were in T2D individuals (Odd Ratio [OR] = 10.88 [95 % confidence interval: 7.33-16.16]), followed by Pre-D (OR = 4.19 [3.02-5.81]), and MU (OR = 3.36 [2.39-4.71]). During a median follow up of 26.7 years (21.2-28.7 years), 3982 died. NAFLD subjects had significantly higher age-adjusted mortality than non-NAFLD (32.7 % vs. 28.7 %, p < .001). Among subjects with NAFLD, the highest age-standardized cumulative mortality was observed among those with T2D (41.3 %), followed by with Pre-D (35.1 %), MU subjects (30.0 %), and MH subjects (21.9 %) (pairwise p-values<.04 vs. MH). Multivariable adjusted cox models showed that NAFLD with T2D had a higher risk of all-causes and cardiac-specific deaths (Hazard Ratio [HR] = 4.71 [2.23-9.96] and HR = 20.01 [3.00-133.61]), followed by NAFLD with Pre-D (HR = 2.91 [1.41-6.02] and HR = 10.35 [1.57-68.08]) and metabolically unhealthy NAFLD (HR = 2.59 [1.26-5.33] and HR = 6.74 [0.99-46.03]) compared to metabolically healthy NAFLD. In addition to older age, independent predictors of mortality among NAFLD with T2D included high CRP, CVD, CKD, high FIB-4, and active smoking. Similarly, among NAFLD with PreD, high CRP, CKD, CVD, hypertension, and active smoking were associated with mortality. Finally, CVD and active smoking were predictors of mortality among metabolically unhealthy NAFLD, and active smoking was the only mortality risk among metabolically healthy NAFLD subjects. INTERPRETATION: Metabolic abnormality impacts both prevalence and outcomes of subjects with NAFLD.
Diet for the prevention and management of sarcopenia.
Calvani R, Picca A, Coelho-Júnior HJ … +3 more , Tosato M, Marzetti E, Landi F
Metabolism · 2023 Sep · PMID 37352971 · Publisher ↗
Sarcopenia is a geriatric condition characterized by a progressive loss of skeletal muscle mass and strength, with an increased risk of adverse health outcomes (e.g., falls, disability, institutionalization, reduced qual...
Sarcopenia is a geriatric condition characterized by a progressive loss of skeletal muscle mass and strength, with an increased risk of adverse health outcomes (e.g., falls, disability, institutionalization, reduced quality of life, mortality). Pharmacological remedies are currently unavailable for preventing the development of sarcopenia, halting its progression, or impeding its negative health outcomes. The most effective strategies to contrast sarcopenia rely on the adoption of healthier lifestyle behaviors, including adherence to high-quality diets and regular physical activity. In this review, the role of nutrition in the prevention and management of sarcopenia is summarized. Special attention is given to current "blockbuster" dietary regimes and agents used to counteract age-related muscle wasting, together with their putative mechanisms of action. Issues related to the design and implementation of effective nutritional strategies are discussed, with a focus on unanswered questions on the most appropriate timing of nutritional interventions to preserve muscle health and function into old age. A brief description is also provided on new technologies that can facilitate the development and implementation of personalized nutrition plans to contrast sarcopenia.
Current and investigational medications for the treatment of sarcopenia.
Rolland Y, Dray C, Vellas B … +1 more , Barreto PS
Metabolism · 2023 Dec · PMID 37348598 · Publisher ↗
Sarcopenia, defined as the loss of muscle mass and function, is a widely prevalent and severe condition in older adults. Since 2016, it is recognized as a disease. Strength exercise training and nutritional support are t...
Sarcopenia, defined as the loss of muscle mass and function, is a widely prevalent and severe condition in older adults. Since 2016, it is recognized as a disease. Strength exercise training and nutritional support are the frontline treatment of sarcopenia, with no drug currently approved for this indication. However, new therapeutic options are emerging. In this review, we evidenced that only very few trials have focused on sarcopenia/sarcopenic patients. Most drug trials were performed in different clinical older populations (e.g., men with hypogonadism, post-menopausal women at risk for osteoporosis), and their efficacy were tested separately on the components of sarcopenia (muscle mass, muscle strength and physical performances). Results from trials testing the effects of Testosterone, Selective Androgen Receptor Modulators (SARMs), Estrogen, Dehydroepiandrosterone (DHEA), Insulin-like Growth Factor-1 (IGF-1), Growth Hormone (GH), GH Secretagogue (GHS), drug targeting Myostatin and Activin receptor pathway, Vitamin D, Angiotensin Converting Enzyme inhibitors (ACEi) and Angiotensin Receptor Blockers (ARBs), or β-blockers, were compiled. Although some drugs have been effective in improving muscle mass and/or strength, this was not translated into clinically relevant improvements on physical performance. Finally, some promising molecules investigated in on-going clinical trials and in pre-clinical phase were summarized, including apelin and irisin.
Sarcopenia, osteoporosis and frailty.
Gielen E, Dupont J, Dejaeger M … +1 more , Laurent MR
Metabolism · 2023 Aug · PMID 37348597 · Publisher ↗
Muscles and bones are intricately connected tissues displaying marked co-variation during development, growth, aging, and in many diseases. While the diagnosis and treatment of osteoporosis are well established in clinic...
Muscles and bones are intricately connected tissues displaying marked co-variation during development, growth, aging, and in many diseases. While the diagnosis and treatment of osteoporosis are well established in clinical practice, sarcopenia has only been classified internationally as a disease in 2016. Both conditions are associated with an increased risk of adverse health outcomes such as fractures, dysmobility and mortality. Rather than focusing on one dimension of bone or muscle mass or weakness, the concept of musculoskeletal frailty captures the overall loss of physiological reserves in the locomotor system with age. The term osteosarcopenia in particular refers to the double jeopardy of osteoporosis and sarcopenia. Muscle-bone interactions at the biomechanical, cellular, paracrine, endocrine, neuronal or nutritional level may contribute to the pathophysiology of osteosarcopenia. The paradigm wherein muscle force controls bone strength is increasingly facing competition from a model centering on the exchange of myokines, osteokines and adipokines. The most promising results have been obtained in preclinical models where common drug targets have been identified to treat these conditions simultaneously. In this narrative review, we critically summarize the current understanding of the definitions, epidemiology, pathophysiology, and treatment of osteosarcopenia as part of an integrative approach to musculoskeletal frailty.
Protective effects of the succinate/SUCNR1 axis on damaged hepatocytes in NAFLD.
Marsal-Beltran A, Rodríguez-Castellano A, Astiarraga B … +21 more , Calvo E, Rada P, Madeira A, Rodríguez-Peña MM, Llauradó G, Núñez-Roa C, Gómez-Santos B, Maymó-Masip E, Bosch R, Frutos MD, Moreno-Navarrete JM, Ramos-Molina B, Aspichueta P, Joven J, Fernández-Real JM, Quer JC, Valverde ÁM, Pardo A, Vendrell J, Ceperuelo-Mallafré V, Fernández-Veledo S
Metabolism · 2023 Aug · PMID 37315889 · Publisher ↗
OBJECTIVE: Succinate and succinate receptor 1 (SUCNR1) are linked to fibrotic remodeling in models of non-alcoholic fatty liver disease (NAFLD), but whether they have roles beyond the activation of hepatic stellate cells...
OBJECTIVE: Succinate and succinate receptor 1 (SUCNR1) are linked to fibrotic remodeling in models of non-alcoholic fatty liver disease (NAFLD), but whether they have roles beyond the activation of hepatic stellate cells remains unexplored. We investigated the succinate/SUCNR1 axis in the context of NAFLD specifically in hepatocytes. METHODS: We studied the phenotype of wild-type and Sucnr1 mice fed a choline-deficient high-fat diet to induce non-alcoholic steatohepatitis (NASH), and explored the function of SUCNR1 in murine primary hepatocytes and human HepG2 cells treated with palmitic acid. Lastly, plasma succinate and hepatic SUCNR1 expression were analyzed in four independent cohorts of patients in different NAFLD stages. RESULTS: Sucnr1 was upregulated in murine liver and primary hepatocytes in response to diet-induced NASH. Sucnr1 deficiency provoked both beneficial (reduced fibrosis and endoplasmic reticulum stress) and detrimental (exacerbated steatosis and inflammation and reduced glycogen content) effects in the liver, and disrupted glucose homeostasis. Studies in vitro revealed that hepatocyte injury increased Sucnr1 expression, which when activated improved lipid and glycogen homeostasis in damaged hepatocytes. In humans, SUCNR1 expression was a good determinant of NAFLD progression to advanced stages. In a population at risk of NAFLD, circulating succinate was elevated in patients with a fatty liver index (FLI) ≥60. Indeed, succinate had good predictive value for steatosis diagnosed by FLI, and improved the prediction of moderate/severe steatosis through biopsy when added to an FLI algorithm. CONCLUSIONS: We identify hepatocytes as target cells of extracellular succinate during NAFLD progression and uncover a hitherto unknown function for SUCNR1 as a regulator of hepatocyte glucose and lipid metabolism. Our clinical data highlight the potential of succinate and hepatic SUCNR1 expression as markers to diagnose fatty liver and NASH, respectively.
Renoprotective effects of genetically proxied fibroblast growth factor 21: Mendelian randomization, proteome-wide and metabolome-wide association study.
Giontella A, Zagkos L, Geybels M … +6 more , Larsson SC, Tzoulaki I, Mantzoros CS, Andersen B, Gill D, Cronjé HT
Metabolism · 2023 Aug · PMID 37302695 · Publisher ↗
BACKGROUND: Fibroblast growth factor 21 (FGF21) has demonstrated efficacy for reducing liver fat and reversing non-alcoholic steatohepatitis in phase 2 clinical trials. It is also postulated to have anti-fibrotic effects...
BACKGROUND: Fibroblast growth factor 21 (FGF21) has demonstrated efficacy for reducing liver fat and reversing non-alcoholic steatohepatitis in phase 2 clinical trials. It is also postulated to have anti-fibrotic effects and therefore may be amenable to repurposing for the prevention and treatment of chronic kidney disease (CKD). METHODS: We leverage a missense genetic variant, rs739320 in the FGF21 gene, that associates with magnetic resonance imaging-derived liver fat as a clinically validated and biologically plausible instrumental variable for studying the effects of FGF21 analogs. Performing Mendelian randomization, we ascertain associations between instrumented FGF21 and kidney phenotypes, cardiometabolic disease risk factors, as well as the circulating proteome (Somalogic, 4907 aptamers) and metabolome (Nightingale platform, 249 metabolites). RESULTS: We report consistent renoprotective associations of genetically proxied FGF21 effect, including higher glomerular filtration rates (p = 1.9 × 10), higher urinary sodium excretion (p = 5.1 × 10), and lower urine albumin-creatinine ratio (p = 3.6 × 10). These favorable effects translated to lower CKD risk (odds ratio per rs739320 C-allele, 0.96; 95%CI, 0.94-0.98; p = 3.2 × 10). Genetically proxied FGF21 effect was also associated with lower fasting insulin, waist-to-hip ratio, blood pressure (systolic and diastolic BP, p < 1.0 × 10) and blood lipid (low-density lipoprotein cholesterol, triglycerides and apolipoprotein B, p < 6.5 × 10) profiles. The latter associations are replicated in our metabolome-wide association study. Proteomic perturbations associated with genetically predicted FGF21 effect were consistent with fibrosis reduction. CONCLUSION: This study highlights the pleiotropic effects of genetically proxied FGF21 and supports a re-purposing opportunity for the treatment and prevention of kidney disease specifically. Further work is required to triangulate these findings, towards possible clinical development of FGF21 towards the treatment and prevention of kidney disease.
Eosinophils protect from metabolic alterations triggered by obesity.
Oliveira MC, Silveira ALM, de Oliveira ACC … +9 more , Lana JP, Costa KA, Vieira ÉLM, Pinho V, Teixeira MM, Merabtene F, Marcelin G, Clément K, Ferreira AVM
Metabolism · 2023 Sep · PMID 37295715 · Publisher ↗
BACKGROUND: Eosinophils are generally related to helminth infections or allergies. Their association with metabolic alterations and adipose tissue (AT) remodeling has been demonstrated mainly in animal models of obesity....
BACKGROUND: Eosinophils are generally related to helminth infections or allergies. Their association with metabolic alterations and adipose tissue (AT) remodeling has been demonstrated mainly in animal models of obesity. However, their physiological role in driving metabolic features has not yet been well described. Herein, we aimed to evaluate the participation of eosinophils in metabolic and adipose tissue homeostasis in mice and humans, focusing on a translational perspective. MATERIAL AND METHODS: Male BALB/c wild-type (WT) mice and GATA-1 knockout (Δdb/GATA-1) mice were followed until 16-week-age in a regular diet or were fed with a high-refined-carbohydrate (HC) diet or high-fat (HF) diet for eight weeks. In subjects with obesity, clinical parameters and omental AT gene expression were evaluated. RESULTS: Eosinophils lack in mice fed a regular diet induced insulin resistance and increased adiposity. Their adipose tissue showed augmented cytokine levels, which could be attributed to increased leukocytes in the tissue, such as neutrophils and pro-inflammatory macrophages. Bone marrow transplant from WT mice to Δdb/GATA-1 mice showed some improvement in glucose metabolism with lower adipose tissue mass accretion. Upon an unhealthy diet challenge, Δdb/GATA-1 mice fed HC diet showed a mild degree of adiposity and glucose metabolic dysfunction severe in those mice fed HF diet. The expression of eosinophil markers in omental AT from humans with severe obesity was positively correlated to eosinophil cytokines and insulin sensitivity surrogate markers and negatively correlated to systemic insulin, HOMA-IR, and android fat mass. CONCLUSIONS: Eosinophils seem to have a physiological role by controlling systemic and adipose tissue metabolic homeostasis by modulating glucose metabolism, inflammation, and visceral fat expansion, even in lean mice. Indeed, eosinophils also seem to modulate glucose homeostasis in human obesity.
Hepatic insulin receptor: new views on the mechanisms of liver disease.
Lee WH, Najjar SM, Kahn CR … +1 more , Hinds TD
Metabolism · 2023 Aug · PMID 37271372 · Full text
Over 65 % of people with obesity display the metabolic-associated fatty liver disease (MAFLD), which can manifest as steatohepatitis, fibrosis, cirrhosis, or liver cancer. The development and progression of MAFLD involve...
Over 65 % of people with obesity display the metabolic-associated fatty liver disease (MAFLD), which can manifest as steatohepatitis, fibrosis, cirrhosis, or liver cancer. The development and progression of MAFLD involve hepatic insulin resistance and reduced insulin clearance. This review discusses the relationships between altered insulin signaling, hepatic insulin resistance, and reduced insulin clearance in the development of MAFLD and how this provides the impetus for exploring the use of insulin sensitizers to curb this disease. The review also explores the role of the insulin receptor in hepatocytes and hepatic stellate cells and how it signals in metabolic and end-stage liver diseases. Finally, we discuss new research findings that indicate that advanced hepatic diseases may be an insulin-sensitive state in the liver and deliberate whether insulin sensitizers should be used to manage late-stage liver diseases.
A polyphenol-rich green Mediterranean diet enhances epigenetic regulatory potential: the DIRECT PLUS randomized controlled trial.
Hoffmann A, Meir AY, Hagemann T … +19 more , Czechowski P, Müller L, Engelmann B, Haange SB, Rolle-Kampczyk U, Tsaban G, Zelicha H, Rinott E, Kaplan A, Shelef I, Stumvoll M, Blüher M, Liang L, Ceglarek U, Isermann B, von Bergen M, Kovacs P, Keller M, Shai I
Metabolism · 2023 Aug · PMID 37236302 · Publisher ↗
BACKGROUND: The capacity of a polyphenol-enriched diet to modulate the epigenome in vivo is partly unknown. Given the beneficial metabolic effects of a Mediterranean (MED) diet enriched in polyphenols and reduced in red/...
BACKGROUND: The capacity of a polyphenol-enriched diet to modulate the epigenome in vivo is partly unknown. Given the beneficial metabolic effects of a Mediterranean (MED) diet enriched in polyphenols and reduced in red/processed meat (green-MED), as previously been proven by the 18-month DIRECT PLUS randomized controlled trial, we analyzed the effects of the green-MED diet on methylome and transcriptome levels to highlight molecular mechanisms underlying the observed metabolic improvements. METHODS: Our study included 260 participants (baseline BMI = 31.2 kg/m, age = 5 years) of the DIRECT PLUS trial, initially randomized to one of the intervention arms: A. healthy dietary guidelines (HDG), B. MED (440 mg polyphenols additionally provided by walnuts), C. green-MED (1240 mg polyphenols additionally provided by walnuts, green tea, and Mankai: green duckweed shake). Blood methylome and transcriptome of all study subjects were analyzed at baseline and after completing the 18-month intervention using Illumina EPIC and RNA sequencing technologies. RESULTS: A total of 1573 differentially methylated regions (DMRs; false discovery rate (FDR) < 5 %) were found in the green-MED compared to the MED (177) and HDG (377) diet participants. This corresponded to 1753 differentially expressed genes (DEGs; FDR < 5 %) in the green-MED intervention compared to MED (7) and HDG (738). Consistently, the highest number (6 %) of epigenetic modulating genes was transcriptionally changed in subjects participating in the green-MED intervention. Weighted cluster network analysis relating transcriptional and phenotype changes among participants subjected to the green-MED intervention identified candidate genes associated with serum-folic acid change (all P < 1 × 10) and highlighted one module including the KIR3DS1 locus, being negatively associated with the polyphenol changes (e.g. P < 1 × 10), but positively associated with the MRI-assessed superficial subcutaneous adipose area-, weight- and waist circumference- 18-month change (all P < 0.05). Among others, this module included the DMR gene Cystathionine Beta-Synthase, playing a major role in homocysteine reduction. CONCLUSIONS: The green-MED high polyphenol diet, rich in green tea and Mankai, renders a high capacity to regulate an individual's epigenome. Our findings suggest epigenetic key drivers such as folate and green diet marker to mediate this capacity and indicate a direct effect of dietary polyphenols on the one‑carbon metabolism.
Fructose induced KHK-C can increase ER stress independent of its effect on lipogenesis to drive liver disease in diet-induced and genetic models of NAFLD.
Park SH, Helsley RN, Fadhul T … +20 more , Willoughby JLS, Noetzli L, Tu HC, Solheim MH, Fujisaka S, Pan H, Dreyfuss JM, Bons J, Rose J, King CD, Schilling B, Lusis AJ, Pan C, Gupta M, Kulkarni RN, Fitzgerald K, Kern PA, Divanovic S, Kahn CR, Softic S
Metabolism · 2023 Aug · PMID 37230214 · Full text
Non-alcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome, and is estimated to affect one billion individuals worldwide. An increased intake of a high-fat diet (HFD) and sugar-sweetened bev...
Non-alcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome, and is estimated to affect one billion individuals worldwide. An increased intake of a high-fat diet (HFD) and sugar-sweetened beverages are risk-factors for NAFLD development, but how their combined intake promotes progression to a more severe form of liver injury is unknown. Here we show that fructose metabolism via ketohexokinase (KHK) C isoform leads to unresolved endoplasmic reticulum (ER) stress when coupled with a HFD intake. Conversely, a liver-specific knockdown of KHK in mice consuming fructose on a HFD is adequate to improve the NAFLD activity score and exert a profound effect on the hepatic transcriptome. Overexpression of KHK-C in cultured hepatocytes is sufficient to induce ER stress in fructose free media. Upregulation of KHK-C is also observed in mice with genetically induced obesity or metabolic dysfunction, whereas KHK knockdown in these mice improves metabolic function. Additionally, in over 100 inbred strains of male or female mice hepatic KHK expression correlates positively with adiposity, insulin resistance, and liver triglycerides. Similarly, in 241 human subjects and their controls, hepatic Khk expression is upregulated in early, but not late stages of NAFLD. In summary, we describe a novel role of KHK-C in triggering ER stress, which offers a mechanistic understanding of how the combined intake of fructose and a HFD propagates the development of metabolic complications.
Direct and systemic actions of growth hormone receptor (GHR)-signaling on hepatic glycolysis, de novo lipogenesis and insulin sensitivity, associated with steatosis.
Vázquez-Borrego MC, Del Río-Moreno M, Pyatkov M … +9 more , Sarmento-Cabral A, Mahmood M, Pelke N, Wnek M, Cordoba-Chacon J, Waxman DJ, Puchowicz MA, McGuinness OP, Kineman RD
Metabolism · 2023 Jul · PMID 37182789 · Full text
BACKGROUND: Evidence is accumulating that growth hormone (GH) protects against the development of steatosis and progression of non-alcoholic fatty liver disease (NAFLD). GH may control steatosis indirectly by altering sy...
BACKGROUND: Evidence is accumulating that growth hormone (GH) protects against the development of steatosis and progression of non-alcoholic fatty liver disease (NAFLD). GH may control steatosis indirectly by altering systemic insulin sensitivity and substrate delivery to the liver and/or by the direct actions of GH on hepatocyte function. APPROACH: To better define the hepatocyte-specific role of GH receptor (GHR) signaling on regulating steatosis, we used a mouse model with adult-onset, hepatocyte-specific GHR knockdown (aHepGHRkd). To prevent the reduction in circulating insulin-like growth factor 1 (IGF1) and the subsequent increase in GH observed after aHepGHRkd, subsets of aHepGHRkd mice were treated with adeno-associated viral vectors (AAV) driving hepatocyte-specific expression of IGF1 or a constitutively active form of STAT5b (STAT5b). The impact of hepatocyte-specific modulation of GHR, IGF1 and STAT5b on carbohydrate and lipid metabolism was studied across multiple nutritional states and in the context of hyperinsulinemic:euglycemic clamps. RESULTS: Chow-fed male aHepGHRkd mice developed steatosis associated with an increase in hepatic glucokinase (GCK) and ketohexokinase (KHK) expression and de novo lipogenesis (DNL) rate, in the post-absorptive state and in response to refeeding after an overnight fast. The aHepGHRkd-associated increase in hepatic KHK, but not GCK and steatosis, was dependent on hepatocyte expression of carbohydrate response element binding protein (ChREBP), in re-fed mice. Interestingly, under clamp conditions, aHepGHRkd also increased the rate of DNL and expression of GCK and KHK, but impaired insulin-mediated suppression of hepatic glucose production, without altering plasma NEFA levels. These effects were normalized with AAV-mediated hepatocyte expression of IGF1 or STAT5b. Comparison of the impact of AAV-mediated hepatocyte IGF1 versus STAT5b in aHepGHRkd mice across multiple nutritional states, indicated the restorative actions of IGF1 are indirect, by improving systemic insulin sensitivity, independent of changes in the liver transcriptome. In contrast, the actions of STAT5b are due to the combined effects of raising IGF1 and direct alterations in the hepatocyte gene program that may involve suppression of BCL6 and FOXO1 activity. However, the direct and IGF1-dependent actions of STAT5b cannot fully account for enhanced GCK activity and lipogenic gene expression observed after aHepGHRkd, suggesting other GHR-mediated signals are involved. CONCLUSION: These studies demonstrate hepatocyte GHR-signaling controls hepatic glycolysis, DNL, steatosis and hepatic insulin sensitivity indirectly (via IGF1) and directly (via STAT5b). The relative contribution of these indirect and direct actions of GH on hepatocytes is modified by insulin and nutrient availability. These results improve our understanding of the physiologic actions of GH on regulating adult metabolism to protect against NAFLD progression.
Sarcopenia in youth.
Jung HN, Jung CH, Hwang YC
Metabolism · 2023 Jul · PMID 37080353 · Publisher ↗
Recent research has revealed causes other than aging that may induce sarcopenia in young people, contrary to the long-studied age-dependent reduction in muscular mass and function. The risk of sarcopenia begins in early...
Recent research has revealed causes other than aging that may induce sarcopenia in young people, contrary to the long-studied age-dependent reduction in muscular mass and function. The risk of sarcopenia begins in early adulthood, resulting in exaggerated muscle dysfunction in later life. Despite its clinical significance, research on youth-onset sarcopenia is still in its infancy. Due to a paucity of epidemiologic data and standardized criteria for sarcopenia in youth, determining the prevalence of sarcopenia in the young population remains challenging. Based on the evidence, >1 in every 10 young adults of most ethnicities is estimated to have sarcopenia. This review summarizes the possible etiologies of sarcopenia in young populations, including metabolic syndrome, physical inactivity, inadequate nutrition, inherent and perinatal factors, vitamin D deficiency, endocrinopathy, an imbalance of gut microbiota, neuromuscular diseases, organ failure, malignancy, and other inflammatory disorders. This is the first review of the current knowledge on the importance, prevalence, diagnosis, and causes of sarcopenia in youth.
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