| 1. |
- Baboota, Ritesh, et al.
(författare)
-
BMP4 and Gremlin 1 regulate hepatic cell senescence during clinical progression of NAFLD/NASH
- 2022
-
Ingår i: Nature Metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 4:8, s. 1007-21
-
Tidskriftsartikel (refereegranskat)abstract
- The role of hepatic cell senescence in human non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is not well understood. To examine this, we performed liver biopsies and extensive characterization of 58 individuals with or without NAFLD/NASH. Here, we show that hepatic cell senescence is strongly related to NAFLD/NASH severity, and machine learning analysis identified senescence markers, the BMP4 inhibitor Gremlin 1 in liver and visceral fat, and the amount of visceral adipose tissue as strong predictors. Studies in liver cell spheroids made from human stellate and hepatocyte cells show BMP4 to be anti-senescent, anti-steatotic, anti-inflammatory and anti-fibrotic, whereas Gremlin 1, which is particularly highly expressed in visceral fat in humans, is pro-senescent and antagonistic to BMP4. Both senescence and anti-senescence factors target the YAP/TAZ pathway, making this a likely regulator of senescence and its effects. We conclude that senescence is an important driver of human NAFLD/NASH and that BMP4 and Gremlin 1 are novel therapeutic targets. Baboota et al. investigate senescence as a driver of human NAFLD/NASH and show the roles of BMP4 and its antagonist Gremlin 1 as anti-senescent and pro-senescent molecules, respectively.
|
|
| 2. |
- Baboota, Ritesh, et al.
(författare)
-
Emerging Role of Bone Morphogenetic Protein 4 in Metabolic Disorders
- 2021
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 70:2, s. 303-312
-
Tidskriftsartikel (refereegranskat)abstract
- Bone morphogenetic proteins (BMPs) are a group of signaling molecules that belong to the TGF-beta superfamily. Initially discovered for their ability to induce bone formation, BMPs are known to play a diverse and critical array of biological roles. We here focus on recent evidence showing that BMP4 is an important regulator of white/beige adipogenic differentiation with important consequences for thermogenesis, energy homeostasis, and development of obesity in vivo. BMP4 is highly expressed in, and released by, human adipose tissue, and serum levels are increased in obesity. Recent studies have now shown BMP4 to play an important role not only for white/beige/brown adipocyte differentiation and thermogenesis but also in regulating systemic glucose homeostasis and insulin sensitivity. It also has important suppressive effects on hepatic glucose production and lipid metabolism. Cellular BMP4 signaling/action is regulated by both ambient cell/systemic levels and several endogenous and systemic BMP antagonists. Reduced BMP4 signaling/action can contribute to the development of obesity, insulin resistance, and associated metabolic disorders. In this article, we summarize the pleiotropic functions of BMP4 in the pathophysiology of these diseases and also consider the therapeutic implications of targeting BMP4 in the prevention/treatment of obesity and its associated complications.
|
|
| 3. |
- Graham, T. E., et al.
(författare)
-
Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects
- 2006
-
Ingår i: N Engl J Med. - 1533-4406. ; 354:24, s. 2552-63
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Insulin resistance has a causal role in type 2 diabetes. Serum levels of retinol-binding protein 4 (RBP4), a protein secreted by adipocytes, are increased in insulin-resistant states. Experiments in mice suggest that elevated RBP4 levels cause insulin resistance. We sought to determine whether serum RBP4 levels correlate with insulin resistance and change after an intervention that improves insulin sensitivity. We also determined whether elevated serum RBP4 levels are associated with reduced expression of glucose transporter 4 (GLUT4) in adipocytes, an early pathological feature of insulin resistance. METHODS: We measured serum RBP4, insulin resistance, and components of the metabolic syndrome in three groups of subjects. Measurements were repeated after exercise training in one group. GLUT4 protein was measured in isolated adipocytes. RESULTS: Serum RBP4 levels correlated with the magnitude of insulin resistance in subjects with obesity, impaired glucose tolerance, or type 2 diabetes and in nonobese, nondiabetic subjects with a strong family history of type 2 diabetes. Elevated serum RBP4 was associated with components of the metabolic syndrome, including increased body-mass index, waist-to-hip ratio, serum triglyceride levels, and systolic blood pressure and decreased high-density lipoprotein cholesterol levels. Exercise training was associated with a reduction in serum RBP4 levels only in subjects in whom insulin resistance improved. Adipocyte GLUT4 protein and serum RBP4 levels were inversely correlated. CONCLUSIONS: RBP4 is an adipocyte-secreted molecule that is elevated in the serum before the development of frank diabetes and appears to identify insulin resistance and associated cardiovascular risk factors in subjects with varied clinical presentations. These findings provide a rationale for antidiabetic therapies aimed at lowering serum RBP4 levels.
|
|
| 4. |
- Hedjazifar, Shahram, 1975, et al.
(författare)
-
The Novel Adipokine Gremlin 1 Antagonizes Insulin Action and Is Increased in Type 2 Diabetes and NAFLD/NASH
- 2020
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 69:3, s. 331-341
-
Tidskriftsartikel (refereegranskat)abstract
- The BMP2/4 antagonist and novel adipokine Gremlin 1 is highly expressed in human adipose cells and increased in hypertrophic obesity. As a secreted antagonist, it inhibits the effect of BMP2/4 on adipose precursor cell commitment/differentiation. We examined mRNA levels of Gremlin 1 in key target tissues for insulin and also measured tissue and serum levels in several carefully phenotyped human cohorts. Gremlin 1 expression was high in adipose tissue, higher in visceral than in subcutaneous tissue, increased in obesity, and further increased in type 2 diabetes (T2D). A similar high expression was seen in liver biopsies, but expression was considerably lower in skeletal muscles. Serum levels were increased in obesity but most prominently in T2D. Transcriptional activation in both adipose tissue and liver as well as serum levels were strongly associated with markers of insulin resistance in vivo (euglycemic clamps and HOMA of insulin resistance), and the presence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). We also found Gremlin 1 to antagonize insulin signaling and action in human primary adipocytes, skeletal muscle, and liver cells. Thus, Gremlin 1 is a novel secreted insulin antagonist and biomarker as well as a potential therapeutic target in obesity and its complications T2D and NAFLD/NASH.
|
|
| 5. |
- Lee, Sunjae, et al.
(författare)
-
Integrated Network Analysis Reveals an Association between Plasma Mannose Levels and Insulin Resistance
- 2016
-
Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 24:1, s. 172-184
-
Tidskriftsartikel (refereegranskat)abstract
- To investigate the biological processes that are altered in obese subjects, we generated cell-specific integrated networks (INs) by merging genome-scale metabolic, transcriptional regulatory and protein-protein interaction networks. We performed genome-wide transcriptomics analysis to determine the global gene expression changes in the liver and three adipose tissues from obese subjects undergoing bariatric surgery and integrated these data into the cell-specific INs. We found dysregulations in mannose metabolism in obese subjects and validated our predictions by detecting mannose levels in the plasma of the lean and obese subjects. We observed significant correlations between plasma mannose levels, BMI, and insulin resistance (IR). We also measured plasma mannose levels of the subjects in two additional different cohorts and observed that an increased plasma mannose level was associated with IR and insulin secretion. We finally identified mannose as one of the best plasma metabolites in explaining the variance in obesity-independent IR.
|
|
| 6. |
- Mardinoglu, Adil, 1982, et al.
(författare)
-
Elevated Plasma Levels of 3-Hydroxyisobutyric Acid Are Associated With Incident Type 2 Diabetes
- 2018
-
Ingår i: Ebiomedicine. - : Elsevier BV. - 2352-3964. ; 27, s. 151-155
-
Tidskriftsartikel (refereegranskat)abstract
- Branched-chain amino acids (BCAAs) metabolite, 3-Hydroxyisobutyric acid (3-HIB) has been identified as a secreted mediator of endothelial cell fatty acid transport and insulin resistance (IR) using animal models. To identify if 3-HIB is a marker of human IR and future risk of developing Type 2 diabetes (T2D), we measured plasma levels of 3-HIB and associated metabolites in around 10,000 extensively phenotyped individuals. The levels of 3-HIB were increased in obesity but not robustly associated with degree of IR after adjusting for BMI. Nevertheless, also after adjusting for obesity and plasma BCAA, 3-HIB levels were associated with future risk of incident T2D. We also examined the effect of 3-HIB on fatty acid uptake in human cells and found that both HUVEC and human cardiac endothelial cells respond to 3-HIB whereas human adipose tissue-derived endothelial cells do not respond to 3-HIB. In conclusion, we found that increased plasma level of 3-HIB is a marker of future risk of T2D and 3-HIB may be important for the regulation of metabolic flexibility in heart and muscles.
|
|
| 7. |
- Mardinoglu, Adil, 1982, et al.
(författare)
-
Plasma Mannose Levels Are Associated with Incident Type 2 Diabetes and Cardiovascular Disease
- 2017
-
Ingår i: Cell Metabolism. - : Elsevier BV. - 1932-7420 .- 1550-4131. ; 26:2, s. 281-283
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Plasma mannose levels are elevated in subjects with insulin resistance independently of obesity. Here, we found that elevated plasma mannose levels are strong markers of future risk of several chronic diseases including T2D, CVD, and albuminuria, and that it may contribute to their development rather than just being a novel biomarker.
|
|
| 8. |
- Nerstedt, Annika, 1960, et al.
(författare)
-
Serine/threonine protein kinase 25 (STK25): a novel negative regulator of lipid and glucose metabolism in rodent and human skeletal muscle
- 2012
-
Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 55:6, s. 1797-1807
-
Tidskriftsartikel (refereegranskat)abstract
- This study investigates the role of serine/threonine protein kinase 25 (STK25), a member of the sterile 20 (STE20) superfamily of kinases, in the regulation of skeletal muscle metabolism. The effect of depleting STK25 in muscle cells was studied by reducing the mRNA and protein content of this target in the rat myoblast cell line L6 by small interfering (si)RNA. The changes in the mRNA and protein levels of several members of the fatty acid oxidative and glucose metabolic pathways were measured by quantitative real-time (qRT)-PCR and western blot. The rate of palmitate oxidation and glucose uptake was measured after transfection with siRNA for . Expression of was also evaluated in skeletal muscle biopsies from 41 white Europid men and women with normal and impaired glucose tolerance and type 2 diabetes using qRT-PCR. We demonstrate that partial depletion of STK25 increases the expression of uncoupling protein 3 (, accompanied by increased lipid oxidation, in myoblasts. In addition, a reduced level of STK25 enhances the expression of (also known as ), (also known as ) and hexokinase 2, and correspondingly, improves insulin-stimulated glucose uptake in muscle cells. Consistent with these results, significantly higher levels were observed in the skeletal muscle of type 2 diabetic patients, compared with individuals with normal glucose tolerance. This is the first study indicating a possible role for STK25 in the regulation of glucose and lipid metabolism in L6 myoblasts. This kinase appears to be an interesting new mediator to be evaluated for therapeutic intervention in type 2 diabetes and related complications, as controlled increase in lipid oxidation and insulin-stimulated glucose uptake in skeletal muscle is favourable and can restore energy balance in metabolically compromised states.
|
|
| 9. |
- Spinelli, Rosa, et al.
(författare)
-
Increased cell senescence in human metabolic disorders
- 2023
-
Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 133:12
-
Forskningsöversikt (refereegranskat)abstract
- Cell senescence (CS) is at the nexus between aging and associated chronic disorders, and aging increases the burden of CS in all major metabolic tissues. However, CS is also increased in adult obesity, type 2 diabetes (T2D), and nonalcoholic fatty liver disease independent of aging. Senescent tissues are characterized by dysfunctional cells and increased inflammation, and both progenitor cells and mature, fully differentiated and nonproliferating cells are afflicted. Recent studies have shown that hyperinsulinemia and associated insulin resistance (IR) promote CS in both human adipose and liver cells. Similarly, increased CS promotes cellular IR, showing their interdependence. Furthermore, the increased adipose CS in T2D is independent of age, BMI, and degree of hyperinsulinemia, suggesting premature aging. These results suggest that senomorphic/senolytic therapy may become important for treating these common metabolic disorders.
|
|
