Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis

Jiang, Zewen; Zhao, Meng; Voilquin, Laetitia; Jung, Yunshin; Aikio, Mari; Sahai, Tanushi; Dou, Florence Y.; Roche, Alexander M.; Cárcamo-Orive, Iván; Knowles, Joshua; Wabitsch, Martin; Appel, Eric A.; Maikawa, Caitlin L.; Camporez, João Paulo; Shulman, Gerald I.; Tsai, Linus; Rosen, Evan D.; Gardner, Christopher D.; Spiegelman, Bruce M.; Svensson, Katrin J.

doi:10.1016/j.cmet.2021.07.010

Cited by 72 publications

(125 citation statements)

References 61 publications

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“…ISM1 has been recently identified in mouse and human adipocytes, regulating glucose uptake while suppressing hepatic lipid synthesis, thus improving hyperglycemia and reducing lipid accumulation in mouse models. Besides, circulating plasma levels of human ISM1 has been detected at an average of 50 pg/mL and trend to positively correlate with BMI, but not with glucose in female individuals [7]. Now, we reveal a relationship between circulating levels of ISM1 and obesity is investigated in a pubertal population.…”

Section: Discussionmentioning

confidence: 82%

“…A recent paper reported that the protein isthmin-1 (ISM1) is secreted by mature adipocytes and triggers a signaling cascade similar to that of insulin. The novel adipokine acts through a unidentified receptor tyrosine kinase and, at pharmacological doses in mice, ISM1 ameliorates metabolic disturbances associated with T2D, including hyperglycemia and liver steatosis [7, 8]. Here, we report that serum levels of the novel insulin-like adipokine ISM1 is, indeed, associated with obesity in pubertal boys, but not in girls in a well-characterized population of Spanish children under a cross-sectional design.…”

Section: Implications and Contributionmentioning

confidence: 80%

“…Group comparisons for ISM1 levels also revealed significant results in boys, although no significant changes were observed when comparing extreme experimental conditions in relation to IR (normal-weight vs. obese with IR). Jiang et al (2021) [7] determined that ISM1 signaling is dependent on PI3K and shares downstream phosphorylation targets with insulin signaling, such as -AKT, p-AKT, p-ERK1/2 and p-S6. Outstandingly, ISM1 activates a PI3K-AKT signaling pathway independently of the insulin and insulin-like growth factor 1 receptors, being most likely to signal through another, yet to be identified, receptor tyrosine kinase.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, in the paper of Jiang et al . (2021) [7], the therapeutic dosing of recombinant ISM1 improves glucose tolerance to the same degree as metformin, enhances diabetes in diet-induced obese mice and ameliorates hepatic steatosis in a diet-induced fatty liver mouse model, establishing that the recombinant Ism1 and its derivatives may be explored for therapeutic purposes and may offer certain advantages over current monotherapies. Nonetheless, the observed higher circulating ISM1 levels in pubertal children suggest that maybe an ISM1 resistance is present, as administration of ISM1 into mice with established disease improves glucose and lipid dysfunction in the diet-induced obesity.…”

Section: Discussionmentioning

confidence: 99%

“…Jiang et al . (2021) [7] determined that ISM1 signaling is dependent on PI3K and shares downstream phosphorylation targets with insulin signaling, such as -AKT, p-AKT, p-ERK1/2 and p-S6. Outstandingly, ISM1 activates a PI3K-AKT signaling pathway independently of the insulin and insulin-like growth factor 1 receptors, being most likely to signal through another, yet to be identified, receptor tyrosine kinase.…”

Section: Discussionmentioning

confidence: 99%

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Serum levels of the novel adipokine isthmin-1 are associated with obesity in pubertal boys

Ruiz‐Ojeda

Anguita‐Ruiz

Rico

et al. 2022

Preprint

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Purpose: The aims of this study were; 1) to evaluate if there is an association between the serum levels of the novel insulin-like adipokine isthmin-1 (ISM1) and obesity-related phenotypes in a population of Spanish children, 2) to investigate the plausible molecular alterations behind the alteration of the serum levels of this protein in children with obesity. Methods: The study population is a sub-cohort of the PUBMEP research project, consisting of a cross-sectional population of 119 pubertal children with overweight (17 boys, 19 girls), obesity (20 boys, 25 girls) and normal weight (17 boys, 21 girls). All subjects were classified into experimental groups according to their sex, obesity and insulin resistance (IR) status. They counted on anthropometry, glucose, and lipid metabolism, inflammation and cardiovascular biomarkers as well as ISM1 serum levels measured. This population was intended as a discovery population in which to elucidate the relationship between obesity and ISM1 levels in children. Furthermore, the study population had blood whole-genome DNA methylation allowing deepening into the obesity-ISM1 molecular relationship. Results: Higher serum levels of ISM1 were observed in boys with obesity when compared with normal-weight (P=0.004), and overweight (P=0.007). ISM1 serum levels were positively associated with BMI Z-score (P=0.005), and negatively with myeloperoxidase (MPO) (p=0.043) in boys. Nevertheless, we did not find associations between ISM1 serum levels and metabolic outcomes in girls, indicating a putative sexual dimorphism. DNA methylation levels in two-enhancer-related CpG sites of ISM1 (cg03304641 and cg14269097) were associated with serum levels of ISM1 in children. Discussion: We report an unprecedented study that provides a major step forward showing that ISM1 is robustly associated with obesity in pubertal boys, elucidating how this protein might be of special relevance as a new biomarker of obesity in children.

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Section: Discussionmentioning

confidence: 82%

Section: Implications and Contributionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Serum levels of the novel adipokine isthmin-1 are associated with obesity in pubertal boys

Ruiz‐Ojeda

Anguita‐Ruiz

Rico

et al. 2022

Preprint

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Isthmin‐1: A critical regulator of branching morphogenesis and metanephric mesenchyme condensation during early kidney development

Gao,

Zhou

2023

BioEssays

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Isthmin‐1 (Ism1) was first described to be syn‐expressed with Fgf8 in Xenopus. However, its biological role has not been elucidated until recent years. Despite of accumulated evidence that Ism1 participates in angiogenesis, tumor invasion, macrophage apoptosis, and glucose metabolism, the cognate receptors for Ism1 remain largely unknown. Ism1 deficiency in mice results in renal agenesis (RA) with a transient loss of Gdnf transcription and impaired mesenchyme condensation at E11.5. Ism1 binds to and activates Integrin α8β1 to positively regulate Gdnf/Ret signaling, thus promoting mesenchyme condensation and ureteric epithelium branching morphogenesis. Here, we propose the hypothesis underlying the mechanism by which Ism1 regulates branching morphogenesis during early kidney development.

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Novel secreted regulators of glucose and lipid metabolism in the development of metabolic diseases

Wat,

Svensson

2024

Diabetologia

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Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis

Cited by 72 publications

References 61 publications

Serum levels of the novel adipokine isthmin-1 are associated with obesity in pubertal boys

Serum levels of the novel adipokine isthmin-1 are associated with obesity in pubertal boys

Isthmin‐1: A critical regulator of branching morphogenesis and metanephric mesenchyme condensation during early kidney development

Novel secreted regulators of glucose and lipid metabolism in the development of metabolic diseases

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