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International Journal of Biological... Apr 2024Combining a Sodium-Glucose-Cotransporter-2-inhibitor (SGLT2i) with metformin is recommended for managing hyperglycemia in patients with type 2 diabetes (T2D) who have...
Combining a Sodium-Glucose-Cotransporter-2-inhibitor (SGLT2i) with metformin is recommended for managing hyperglycemia in patients with type 2 diabetes (T2D) who have cardio-renal complications. Our study aimed to investigate the metabolic effects of SGLT2i and metformin, both individually and synergistically. We treated leptin receptor-deficient (db/db) mice with these drugs for two weeks and conducted metabolite profiling, identifying 861 metabolites across kidney, liver, muscle, fat, and plasma. Using linear regression and mixed-effects models, we identified two SGLT2i-specific metabolites, X-12465 and 3-hydroxybutyric acid (3HBA), a ketone body, across all examined tissues. The levels of 3HBA were significantly higher under SGLT2i monotherapy compared to controls and were attenuated when combined with metformin. We observed similar modulatory effects on metabolites involved in protein catabolism (e.g., branched-chain amino acids) and gluconeogenesis. Moreover, combination therapy significantly raised pipecolate levels, which may enhance mTOR1 activity, while modulating GSK3, a common target of SGLT2i and 3HBA inhibition. The combination therapy also led to significant reductions in body weight and lactate levels, contrasted with monotherapies. Our findings advocate for the combined approach to better manage muscle loss, and the risks of DKA and lactic acidosis, presenting a more effective strategy for T2D treatment.
Topics: Mice; Animals; Humans; Metformin; Diabetes Mellitus, Type 2; 3-Hydroxybutyric Acid; Lactic Acid; Glycogen Synthase Kinase 3; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 38503370
DOI: 10.1016/j.ijbiomac.2024.130962 -
Molecular Metabolism May 2024The glucose-dependent insulinotropic polypeptide (GIP) decreases body weight via central GIP receptor (GIPR) signaling, but the underlying mechanisms remain largely...
OBJECTIVE
The glucose-dependent insulinotropic polypeptide (GIP) decreases body weight via central GIP receptor (GIPR) signaling, but the underlying mechanisms remain largely unknown. Here, we assessed whether GIP regulates body weight and glucose control via GIPR signaling in cells that express the leptin receptor (Lepr).
METHODS
Hypothalamic, hindbrain, and pancreatic co-expression of Gipr and Lepr was assessed using single cell RNAseq analysis. Mice with deletion of Gipr in Lepr cells were generated and metabolically characterized for alterations in diet-induced obesity (DIO), glucose control and leptin sensitivity. Long-acting single- and dual-agonists at GIPR and GLP-1R were further used to assess drug effects on energy and glucose metabolism in DIO wildtype (WT) and Lepr-Gipr knock-out (KO) mice.
RESULTS
Gipr and Lepr show strong co-expression in the pancreas, but not in the hypothalamus and hindbrain. DIO Lepr-Gipr KO mice are indistinguishable from WT controls related to body weight, food intake and diet-induced leptin resistance. Acyl-GIP and the GIPR:GLP-1R co-agonist MAR709 remain fully efficacious to decrease body weight and food intake in DIO Lepr-Gipr KO mice. Consistent with the demonstration that Gipr and Lepr highly co-localize in the endocrine pancreas, including the β-cells, we find the superior glycemic effect of GIPR:GLP-1R co-agonism over single GLP-1R agonism to vanish in Lepr-Gipr KO mice.
CONCLUSIONS
GIPR signaling in cells/neurons that express the leptin receptor is not implicated in the control of body weight or food intake, but is of crucial importance for the superior glycemic effects of GIPR:GLP-1R co-agonism relative to single GLP-1R agonism.
Topics: Animals; Male; Mice; Body Weight; Eating; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Leptin; Mice, Inbred C57BL; Mice, Knockout; Obesity; Receptors, Gastrointestinal Hormone; Receptors, Leptin; Signal Transduction
PubMed: 38492844
DOI: 10.1016/j.molmet.2024.101915 -
Clinical Medicine Insights.... 2024Obesity and diabetes mellitus are prevalent metabolic disorders that have a detrimental impact on overall health. In this regard, there is now a clear link between these... (Review)
Review
Obesity and diabetes mellitus are prevalent metabolic disorders that have a detrimental impact on overall health. In this regard, there is now a clear link between these metabolic disorders and compromised bone health. Interestingly, both obesity and diabetes lead to elevated risk of bone fracture which is independent of effects on bone mineral density (BMD). In this regard, gastrointestinal (GIT)-derived peptide hormones and their related long-acting analogues, some of which are already clinically approved for diabetes and/or obesity, also seem to possess positive effects on bone remodelling and microarchitecture to reduce bone fracture risk. Specifically, the incretin peptides, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), as well as glucagon-like peptide-2 (GLP-2), exert key direct and/or indirect benefits on bone metabolism. This review aims to provide an initial appraisal of the relationship between obesity, diabetes and bone, with a focus on the positive impact of these GIT-derived peptide hormones for bone health in obesity/diabetes. Brief discussion of related peptides such as parathyroid hormone, leptin, calcitonin and growth hormone is also included. Taken together, drugs engineered to promote GIP, GLP-1 and GLP-2 receptor signalling may have potential to offer therapeutic promise for improving bone health in obesity and diabetes.
PubMed: 38486712
DOI: 10.1177/11795514241238059 -
International Journal of Molecular... Mar 2024Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a prevalent clinical condition associated with elevated morbidity and mortality rates. Patients with...
Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a prevalent clinical condition associated with elevated morbidity and mortality rates. Patients with MASLD treated with semaglutide, a glucagon-like peptide-1 receptor agonist, demonstrate improvement in terms of liver damage. However, the mechanisms underlaying this beneficial effect are not yet fully elucidated. We investigated the efficacy of semaglutide in halting MASLD progression using a genetic mouse model of diabesity. Leptin-receptor-deficient mice with obesity and diabetes (BKS db/db) were either untreated or administered with semaglutide for 11 weeks. Changes in food and water intake, body weight and glycemia were monitored throughout the study. Body fat composition was assessed by dual-energy X-ray absorptiometry. Upon sacrifice, serum biochemical parameters, liver morphology, lipidomic profile and liver-lipid-related pathways were evaluated. The semaglutide-treated mice exhibited lower levels of glycemia, body weight, serum markers of liver dysfunction and total and percentage of fat mass compared to untreated db/db mice without a significant reduction in food intake. Histologically, semaglutide reduced hepatic steatosis, hepatocellular ballooning and intrahepatic triglycerides. Furthermore, the treatment ameliorated the hepatic expression of de novo lipogenesis markers and modified lipid composition by increasing the amount of polyunsaturated fatty acids. The administration of semaglutide to leptin-receptor-deficient, hyperphagic and diabetic mice resulted in the amelioration of MASLD, likely independently of daily caloric intake, suggesting a direct effect of semaglutide on the liver through modulation of the lipid profile.
Topics: Humans; Animals; Mice; Lipogenesis; Leptin; Diabetes Mellitus, Experimental; Fatty Liver; Obesity; Liver; Body Weight; Triglycerides; Diabetes Mellitus, Type 2; Non-alcoholic Fatty Liver Disease; Mice, Obese; Glucagon-Like Peptides
PubMed: 38474208
DOI: 10.3390/ijms25052961 -
Endocrine Connections May 2024Chronic inflammation induced by obesity plays a crucial role in the pathogenesis of insulin resistance. The infiltration of macrophages into adipose tissues contributes...
Chronic inflammation induced by obesity plays a crucial role in the pathogenesis of insulin resistance. The infiltration of macrophages into adipose tissues contributes to adipose tissue inflammation and insulin resistance. Kaempferol, a flavonoid present in various vegetables and fruits, has been shown to possess remarkable anti-inflammatory properties. In this study, we used leptin receptor-deficient obese mice (db/db) as an insulin-resistant model and investigated the effects of kaempferol treatment on obesity-induced insulin resistance. Our findings revealed that the administration of kaempferol (50 mg/kg/day, for 6 weeks) significantly reduced body weight, fat mass, and adipocyte size. Moreover, it effectively ameliorated abnormal glucose tolerance and insulin resistance in db/db mice. In the adipose tissue of obese mice treated with kaempferol, we observed a reduction in macrophage infiltration and a downregulation of mRNA expression of M1 marker genes TNF-α and IL-1β, accompanied by an upregulation of Arg1 and IL-10 mRNA expression. Additionally, kaempferol treatment significantly inhibited the STING/NLRP3 signaling pathway in adipose tissue. In vitro experiments, we further discovered that kaempferol treatment suppressed LPS-induced inflammation through the activation of NLRP3/caspase 1 signaling in RAW 264.7 macrophages. Our results suggest that kaempferol may effectively alleviate inflammation and insulin resistance in the adipose tissue of db/db mice by modulating the STING/NLRP3 signaling pathway.
PubMed: 38466634
DOI: 10.1530/EC-23-0379 -
Cell Reports Mar 2024Iron overload is closely associated with metabolic dysfunction. However, the role of iron in the hypothalamus remains unclear. Here, we find that hypothalamic iron...
Iron overload is closely associated with metabolic dysfunction. However, the role of iron in the hypothalamus remains unclear. Here, we find that hypothalamic iron levels are increased, particularly in agouti-related peptide (AgRP)-expressing neurons in high-fat-diet-fed mice. Using pharmacological or genetic approaches, we reduce iron overload in AgRP neurons by central deferoxamine administration or transferrin receptor 1 (Tfrc) deletion, ameliorating diet-induced obesity and related metabolic dysfunction. Conversely, Tfrc-mediated iron overload in AgRP neurons leads to overeating and adiposity. Mechanistically, the reduction of iron overload in AgRP neurons inhibits AgRP neuron activity; improves insulin and leptin sensitivity; and inhibits iron-induced oxidative stress, endoplasmic reticulum stress, nuclear factor κB signaling, and suppression of cytokine signaling 3 expression. These results highlight the critical role of hypothalamic iron in obesity development and suggest targets for treating obesity and related metabolic disorders.
Topics: Mice; Animals; Agouti-Related Protein; Obesity; Hypothalamus; Leptin; Neurons; Diet, High-Fat; Iron Overload; Metabolic Diseases; Iron; Mice, Inbred C57BL
PubMed: 38460132
DOI: 10.1016/j.celrep.2024.113900 -
Immunity & Ageing : I & A Mar 2024Several risk factors have been involved in the poor clinical progression of coronavirus disease-19 (COVID-19), including ageing, and obesity. SARS-CoV-2 may compromise...
BACKGROUND
Several risk factors have been involved in the poor clinical progression of coronavirus disease-19 (COVID-19), including ageing, and obesity. SARS-CoV-2 may compromise lung function through cell damage and paracrine inflammation; and obesity has been associated with premature immunosenescence, microbial translocation, and dysfunctional innate immune responses leading to poor immune response against a range of viruses and bacterial infections. Here, we have comprehensively characterized the immunosenescence, microbial translocation, and immune dysregulation established in hospitalized COVID-19 patients with different degrees of body weight.
RESULTS
Hospitalised COVID-19 patients with overweight and obesity had similarly higher plasma LPS and sCD14 levels than controls (all p < 0.01). Patients with obesity had higher leptin levels than controls. Obesity and overweight patients had similarly higher expansions of classical monocytes and immature natural killer (NK) cells (CD56CD16) than controls. In contrast, reduced proportions of intermediate monocytes, mature NK cells (CD56CD16), and NKT were found in both groups of patients than controls. As expected, COVID-19 patients had a robust expansion of plasmablasts, contrasting to lower proportions of major T-cell subsets (CD4 + and CD8+) than controls. Concerning T-cell activation, overweight and obese patients had lower proportions of CD4CD38 cells than controls. Contrasting changes were reported in CD25CD127 regulatory T cells, with increased and decreased proportions found in CD4 and CD8 T cells, respectively. There were similar proportions of T cells expressing checkpoint inhibitors across all groups. We also investigated distinct stages of T-cell differentiation (early, intermediate, and late-differentiated - TEMRA). The intermediate-differentiated CD4 + T cells and TEMRA cells (CD4 and CD8) were expanded in patients compared to controls. Senescent T cells can also express NK receptors (NKG2A/D), and patients had a robust expansion of CD8CD57NKG2A cells than controls. Unbiased immune profiling further confirmed the expansions of senescent T cells in COVID-19.
CONCLUSIONS
These findings suggest that dysregulated immune cells, microbial translocation, and T-cell senescence may partially explain the increased vulnerability to COVID-19 in subjects with excess of body weight.
PubMed: 38454515
DOI: 10.1186/s12979-024-00423-6 -
Cell Metabolism May 2024Obesity is often associated with aging. However, the mechanism of age-related obesity is unknown. The melanocortin-4 receptor (MC4R) mediates leptin-melanocortin...
Obesity is often associated with aging. However, the mechanism of age-related obesity is unknown. The melanocortin-4 receptor (MC4R) mediates leptin-melanocortin anti-obesity signaling in the hypothalamus. Here, we discovered that MC4R-bearing primary cilia of hypothalamic neurons progressively shorten with age in rats, correlating with age-dependent metabolic decline and increased adiposity. This "age-related ciliopathy" is promoted by overnutrition-induced upregulation of leptin-melanocortin signaling and inhibited or reversed by dietary restriction or the knockdown of ciliogenesis-associated kinase 1 (CILK1). Forced shortening of MC4R-bearing cilia in hypothalamic neurons by genetic approaches impaired neuronal sensitivity to melanocortin and resulted in decreased brown fat thermogenesis and energy expenditure and increased appetite, finally developing obesity and leptin resistance. Therefore, despite its acute anti-obesity effect, chronic leptin-melanocortin signaling increases susceptibility to obesity by promoting the age-related shortening of MC4R-bearing cilia. This study provides a crucial mechanism for age-related obesity, which increases the risk of metabolic syndrome.
Topics: Animals; Receptor, Melanocortin, Type 4; Cilia; Obesity; Neurons; Leptin; Rats; Male; Signal Transduction; Hypothalamus; Aging; Rats, Sprague-Dawley; Mice; Energy Metabolism; Adipose Tissue, Brown; Thermogenesis
PubMed: 38452767
DOI: 10.1016/j.cmet.2024.02.010 -
Science Advances Mar 2024Mutations that perturb leptin-melanocortin signaling are known to cause hyperphagia and obesity, but energy expenditure has not been well studied outside rodents. We...
Mutations that perturb leptin-melanocortin signaling are known to cause hyperphagia and obesity, but energy expenditure has not been well studied outside rodents. We report on a common canine mutation in pro-opiomelanocortin (), which prevents production of β-melanocyte-stimulating hormone (β-MSH) and β-endorphin but not α-MSH; humans, similar to dogs, produce α-MSH and β-MSH from the propeptide, but rodents produce only α-MSH. We show that energy expenditure is markedly lower in affected dogs, which also have increased motivational salience in response to a food cue, indicating increased wanting or hunger. There was no difference in satiety at a modified ad libitum meal or in their hedonic response to food, nor disruption of adrenocorticotropic hormone (ACTH) or thyroid axes. In vitro, we show that β-MSH signals comparably to α-MSH at melanocortin receptors. These data implicate β-MSH and β-endorphin as important in determining hunger and moderating energy expenditure and suggest that this role is independent of the presence of α-MSH.
Topics: Humans; Dogs; Animals; beta-Endorphin; beta-MSH; Basal Metabolism; Pro-Opiomelanocortin; Hunger; alpha-MSH
PubMed: 38446876
DOI: 10.1126/sciadv.adj3823 -
European Review For Medical and... Feb 2024The prevalence of both atrial fibrillation (AF) and diabetes is increasing day by day and commonly co-exist with a longer duration of diabetes and poor control, putting... (Review)
Review
The prevalence of both atrial fibrillation (AF) and diabetes is increasing day by day and commonly co-exist with a longer duration of diabetes and poor control, putting the individual at higher risk of AF. This review article presented some traditional and novel biomarkers related to AF in patients with diabetes mellitus. The literature review employed several databases, including Google Scholar, PubMed, and Science Direct. The investigation was finished on October 30, 2023. Many terms are utilized, including "AF", "Biomarkers", "Diabetes Mellitus", and "Pathogenesis". There are numerous biomarkers of diabetes, but this review article reports only leptin, adiponectin, glycated hemoglobin, ceramide, ferritin, fibrinogen, hematological indices, interleukin-18, thrombospondin 1, acylcarnitine, plasminogen activator inhibitor-1 and triglycerides and high-density lipoprotein cholesterol, since those biomarkers play a significant role in the pathogenesis of AF. However, no data was found, including fructosamine, glycated albumin, 1,5 anhydroglucitol, fetuin-A, α-hydroxybutyrate, mannose-binding lectin serine peptidase, transferrin, IL-1 receptor antagonist in AF. Understanding the interplay between diabetes and AF through the measurement of relevant biomarkers can contribute to better risk assessment, early detection, and the development of targeted therapeutic strategies for individuals at risk or already affected by these conditions.
Topics: Humans; Atrial Fibrillation; Diabetes Mellitus; Adiponectin; Biomarkers; Ceramides
PubMed: 38436186
DOI: 10.26355/eurrev_202402_35482