Alarmin high-mobility group B1 (HMGB1) is regulated in human adipocytes in insulin resistance and influences insulin secretion in β-cells

Guzmán‐Ruiz, Rocío; Ortega, Francisco; Rodríguez, Amaia; Vázquez-Martı́nez, Rafael; Díaz‐Ruiz, Alberto; García‐Navarro, Socorro; Giralt, Marta; García‐Rios, Antonio; Cobo-Padilla, D; Tinahones, Francisco J.; López‐Miranda, José; Villarroya, Francesc; Frühbeck, Gema; Fernández-Real, José Manuel; Malagón, Marı́a M.

doi:10.1038/ijo.2014.36

Cited by 80 publications

(59 citation statements)

References 48 publications

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“…This finding is not extremely surprising since HMGB1 and -2, as damage-associated molecular pattern molecules, are late mediators of noninfectious systemic inflammation. Recently, a study conducted in humans demonstrated that the intracellular distribution of HMGB1 is modified in a state of insulin resistance and that HMGB1 is a stimulatory factor of ␤-pancreatic cell insulin secretion, supporting a role for inflammation regulators in glucose homeostasis (17). Moreover, a strong association between HMGB1 and liver disease has been reported previously (7), even if the role of HMGB1 in the association between metabolic distress and liver disease is not fully understood.…”

Section: E752 Liver Protein Profiles In Diabetesmentioning

confidence: 97%

Liver protein profiles in insulin receptor-knockout mice reveal novel molecules involved in the diabetes pathophysiology

Capuani

Della-Morte

Donadel

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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It is under a complex control by substrates such as hormones, nutrients, and neuronal impulses. Insulin promotes glycogen synthesis, lipogenesis, and lipoprotein synthesis and inhibits gluconeogenesis, glycogenolysis, and VLDL secretion by modifying the expression and enzymatic activity of specific molecules. To understand the pathophysiological mechanisms leading to metabolic liver disease, we analyzed liver protein patterns expressed in a mouse model of diabetes by proteomic approaches. We used insulin receptor-knockout (IR Ϫ/Ϫ ) and heterozygous (IR ϩ/Ϫ ) mice as a murine model of liver metabolic dysfunction associated with diabetic ketoacidosis and insulin resistance. We evaluated liver fatty acid levels by microscopic examination and protein expression profiles by orthogonal experimental strategies using protein 2-DE MALDI-TOF/TOF and peptic nLC-MS/MS shotgun profiling. Identified proteins were then loaded into Ingenuity Pathways Analysis to find possible molecular networks. Twenty-eight proteins identified by 2-DE analysis and 24 identified by nLC-MS/MS shotgun were differentially expressed among the three genotypes. Bioinformatic analysis revealed a central role of high-mobility group box 1/2 and huntigtin never reported before in association with metabolic and related liver disease. A different modulation of these proteins in both blood and hepatic tissue further suggests their role in these processes. These results provide new insight into pathophysiology of insulin resistance and hepatic steatosis and could be useful in identifying novel biomarkers to predict risk for diabetes and its complications. insulin resistance; huntigtin; high-mobility group-B1; proteomics TYPE 2 DIABETES (T2D) is a complex metabolic disorder characterized by increased levels of insulin resistance and impaired ␤-cell function with reduced insulin secretion (35). In T2D, modification of hepatic metabolism is associated with glucose and lipid overproduction, leading to overt hyperglycemia and diabetic dyslipidemia. Glucose overproduction is a physiological response in T2D, whereas the overproduction of lipids linked with insulin resistance remains a phenomenon to clarify since insulin increases abundance of lipogenic enzymes and insulin resistance diminishes lipogenesis (31, 41). Furthermore, insulin resistance and T2D are linked with hepatic steatosis, which is an exacerbation of liver dysfunction generated by accumulation of lipids, mainly triglycerides (23).Several etiological mechanisms have been proposed to explain the pathological link between insulin resistance, T2D, and liver disease, including inflammation and oxidative stress (36). Recently, novel anti-inflammatory proteins called chaperones and Toll-like receptors (TLRs) have been suggested to play a significant role in this pathological process (27). However, to date, the molecular mechanisms linking the impairment in glucose homeostasis with liver disease are not fully understood.Therefore, elucidation of molecular alterations, which regulate metabolic liver dysfunct...

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Section: E752 Liver Protein Profiles In Diabetesmentioning

confidence: 97%

Liver protein profiles in insulin receptor-knockout mice reveal novel molecules involved in the diabetes pathophysiology

Capuani

Della-Morte

Donadel

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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“…Many studies have shown the positive correlation between circulating HMGB1 levels and BMI [8][9][10] and it has been also reported that the expression of HMGB1 in adipose tissue is altered in case of obesity. 3,8,11 This difference in HMGB1 expression has been attributed to inflammation insofar as it triggers HMGB1 secretion from cells derived from the stromal fraction of adipose tissue (ASCs), whereas mature adipocytes do not contribute to this secretion.…”

Section: Discussionmentioning

confidence: 99%

“…3,8,11 This difference in HMGB1 expression has been attributed to inflammation insofar as it triggers HMGB1 secretion from cells derived from the stromal fraction of adipose tissue (ASCs), whereas mature adipocytes do not contribute to this secretion. 3 Here we investigated the effects of exogenous disulfide HMGB1 on cultured primary human adipocytes and our results prove that HMGB1 may contribute to chronic and low grade inflammation by its effect on adipocytes, as it has been demonstrated in SW872 pre-adipocytes.…”

Section: Discussionmentioning

confidence: 99%

TLR4-dependant pro-inflammatory effects of HMGB1 on human adipocyte

et al. 2016

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Chronic low grade inflammation is one of the major metabolic disorders in case of obesity and associated pathologies. By its important secretion function, the role of adipose tissue in this metabolic low grade inflammation is well known. Recently, it was demonstrated that the alarmin high mobility group box protein 1 (HMGB1) is involved in obesity-related pathologies by its increased serum levels in obese compared to normal weight individuals, and by its proinflammatory effects. However, the role of HMGB1 on adipocytes inflammation is poorly documented and we propose to investigate this point. Primary culture of human subcutaneous adipocytes were performed from human adipose tissue samples. Cells were treated with recombinant HMGB1 with/without anti-TLR4 antibody and inhibitors of NF-kB and P38 MAPK. Supernatants were collected for IL-6 and MCP-1 ELISA. HMGB1 initiates Toll-like receptor 4 (TLR4)-dependent activation of inflammation through the downstream NF-kB and P38 MAPK signaling pathway to upregulate the secretion of the pro-inflammatory cytokine IL-6. HMGB1 has proinflammatory effects on adipocytes. This reinforces the role of TLR4 in adipose tissue inflammation and antagonizing the HMGB1 inflammatory pathway could bring on new therapeutic targets to counteract obesity-associated pathologies.

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“…Circulating HMGB1 is positively associated with body mass index, while adipose HMGB1 mRNA levels correlate with the expression of inflammatory markers [24]. Insulin resistance modifies the intracellular distribution of HMGB1 in human adipocytes, with HMGB1 being predominantly nuclear in lean and obese normoglycemic individuals while localized to the cytosol in obese type 2 diabetic patients, and HMGB1 acts as a stimulatory factor of insulin secretion of β-cells [24]. HMGB1 is suggested to act as an adipokine contributing to low-grade inflammation in fat tissue [25].…”

Section: Discussionmentioning

confidence: 97%

“…Several reports indicate that HMGB1 is a pro-inflammatory cytokine which may contribute to the pathogenesis of micro-and macrovascular complications in diabetes [18][19][20][21][22][23]. Circulating HMGB1 is positively associated with body mass index, while adipose HMGB1 mRNA levels correlate with the expression of inflammatory markers [24]. Insulin resistance modifies the intracellular distribution of HMGB1 in human adipocytes, with HMGB1 being predominantly nuclear in lean and obese normoglycemic individuals while localized to the cytosol in obese type 2 diabetic patients, and HMGB1 acts as a stimulatory factor of insulin secretion of β-cells [24].…”

Section: Discussionmentioning

confidence: 97%

Irbesartan attenuates production of high-mobility group box 1 in response to lipopolysaccharide via downregulation of interferon-β production

Kato

Kawanishi

Koide

et al. 2015

International Immunopharmacology

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Alarmin high-mobility group B1 (HMGB1) is regulated in human adipocytes in insulin resistance and influences insulin secretion in β-cells

Cited by 80 publications

References 48 publications

Liver protein profiles in insulin receptor-knockout mice reveal novel molecules involved in the diabetes pathophysiology

Liver protein profiles in insulin receptor-knockout mice reveal novel molecules involved in the diabetes pathophysiology

TLR4-dependant pro-inflammatory effects of HMGB1 on human adipocyte

Irbesartan attenuates production of high-mobility group box 1 in response to lipopolysaccharide via downregulation of interferon-β production

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