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

Ruiz‐Ojeda, Francisco Javier; Anguita‐Ruiz, Augusto; Rico, María C; Leis, Rosaura; Bueno, Gloria; Gil‐Campos, Mercedes; Gil, Ángel; Aguilera, Concepción M.

doi:10.1101/2022.03.02.22271664

Cited by 4 publications

(6 citation statements)

References 21 publications

(29 reference statements)

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“…Notably, Ism1 itself is not expressed in muscle cells but only in other cells, including adipocytes and immune cells. Circulating levels of human Ism1 using immunoreactive ELISAs have been reported to be in the range of 1–50 ng/ml ( Jiang et al, 2021 ; Ruiz-Ojeda et al, 2022 ), consistent with mass spectrometry peptide analysis that estimates a circulating Ism1 concentration of 17 ng/ml ( Uhlén et al, 2019 ). The necessary circulating and local Ism1 levels to maintain muscle fiber size or prevent fasting-induced muscle loss remain to be determined.…”

Section: Discussionsupporting

confidence: 67%

“…To globally discern possible pathways activated by Ism1 and possible grouping of functional effects, we conducted GO enrichment analysis using biological processes coupled with visualization by semantic similarity. We found associations previously linked to Ism1, including metabolic processes such as glucose and lipid metabolism ( Jiang et al, 2021 ; Ruiz-Ojeda et al, 2022 ), nervous system development ( Osório et al, 2014 ; Pera et al, 2002 ), and the immune system ( Lam et al, 2022 ; Li et al, 2021 ; Valle-Rios et al, 2014 ; Wu et al, 2021 ; Figure 2P ). Intriguingly, also here, we identify several pathways associated with muscle, skeletal muscle, and cardiac muscle in the Ism1 treatment group ( Figure 2P ).…”

Section: Resultsmentioning

confidence: 59%

“…We recently reported that the adipocyte-secreted protein isthmin-1 (Ism1) improves glucose tolerance and insulin resistance by phosphorylating Akt S473 , which mediates increased adipose and skeletal muscle glucose uptake ( Jiang et al, 2021 ). Ism1 adipose expression and circulating levels are elevated in mice and humans with obesity ( Jiang et al, 2021 ; Ruiz-Ojeda et al, 2022 ), suggesting that the expression is under nutrient-sensing regulatory control. Intriguingly, Ism1 administration to mice simultaneously prevents hepatic lipid accumulation while increasing protein synthesis in hepatocytes ( Jiang et al, 2021 ), demonstrating that Ism1 governs an anabolic pathway that is molecularly and functionally distinct from insulin.…”

Section: Introductionmentioning

confidence: 99%

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Phosphoproteomic mapping reveals distinct signaling actions and activation of muscle protein synthesis by Isthmin-1

Zhao

Dannieskiold-Samsøe

Ulicna

et al. 2022

eLife

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The secreted protein Isthmin-1 (Ism1) mitigates diabetes by increasing adipocyte and skeletal muscle glucose uptake by activating the PI3K-Akt pathway. However, while both Ism1 and insulin converge on these common targets, Ism1 has distinct cellular actions suggesting divergence in downstream intracellular signaling pathways. To understand the biological complexity of Ism1 signaling, we performed phosphoproteomic analysis after acute exposure, revealing overlapping and distinct pathways of Ism1 and insulin. We identify a 53 % overlap between Ism1 and insulin signaling and Ism1-mediated phosphoproteome-wide alterations in ~ 450 proteins that are not shared with insulin. Interestingly, we find several unknown phosphorylation sites on proteins related to protein translation, mTOR pathway and, unexpectedly, muscle function in the Ism1 signaling network. Physiologically, Ism1 ablation in mice results in altered proteostasis, including lower muscle protein levels under fed and fasted conditions, reduced amino acid incorporation into proteins, and reduced phosphorylation of the key protein synthesis effectors Akt and downstream mTORC1 targets. As metabolic disorders such as diabetes are associated with accelerated loss of skeletal muscle protein content, these studies define a non-canonical mechanism by which this anti-diabetic circulating protein controls muscle biology.

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Section: Discussionsupporting

confidence: 67%

Section: Resultsmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Phosphoproteomic mapping reveals distinct signaling actions and activation of muscle protein synthesis by Isthmin-1

Zhao

Dannieskiold-Samsøe

Ulicna

et al. 2022

eLife

View full text Add to dashboard Cite

show abstract

“…Notably, Ism1 itself is not expressed in muscle cells but only in other cells, including adipocytes and immune cells. Circulating levels of human ISM1 using immunoreactive ELISAs have been reported to be in the range of 1-50 ng/ml (Jiang et al, 2021; Ruiz-Ojeda et al, 2022), consistent with mass spectrometry peptide analysis which estimates a circulating ISM1 concentration of 17 ng/ml (Uhlén et al, 2019). The necessary circulating and local Ism1 levels to maintain muscle fiber size or prevent fasting-induced muscle loss remain to be determined.…”

Section: Discussionsupporting

confidence: 64%

“…To globally discern possible pathways activated by Ism1 and possible grouping of functional effects, we conducted GO enrichment analysis using biological processes coupled with visualization by semantic similarity. We found associations previously linked to Ism1, including metabolic processes such as glucose and lipid metabolism (Jiang et al, 2021;Ruiz-Ojeda et al, 2022), nervous system development (Osoŕio et al, 2014;Pera et al, 2002), and the immune system (Lam et al, 2022;Li et al, 2021;Valle-Rios et al, 2014;Wu et al, 2021) (Figure 2P).…”

Section: Phospho-specific Mapping Identifies An Ism1-induced Signatur...supporting

confidence: 59%

Phosphoproteomic mapping reveals distinct signaling actions and activation of protein synthesis and muscle hypertrophy by Isthmin-1

Zhao

Danneskiold‐Samsøe

Ulicna

et al. 2022

Preprint

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The secreted protein Isthmin-1 (Ism1) mitigates diabetes by increasing adipocyte and skeletal muscle glucose uptake by activating the PI3K-Akt pathway. However, while both Ism1 and insulin converge on these common targets, Ism1 has distinct cellular actions suggesting divergence in downstream intracellular signaling pathways. To understand the biological complexity of Ism1 signaling, we performed phosphoproteomic analysis after acute exposure, revealing overlapping and distinct pathways of Ism1 and insulin. We identify a 53 % overlap between Ism1 and insulin signaling and Ism1-mediated phosphoproteome-wide alterations in ∼ 450 proteins that are not shared with insulin. Interestingly, we find several unknown phosphorylation sites on proteins related to protein translation, mTOR pathway and, unexpectedly, muscle function in the Ism1 signaling network. Physiologically, Ism1 ablation in mice results in altered proteostasis, including lower muscle protein levels under fed and fasted conditions, reduced amino acid incorporation into proteins, and reduced phosphorylation of the key protein synthesis effectors Akt and downstream mTORC1 targets. As metabolic disorders such as diabetes are associated with accelerated loss of skeletal muscle protein content, these studies define a non-canonical mechanism by which this anti-diabetic circulating protein controls muscle biology.

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Isthmin—A Multifaceted Protein Family

Shakhawat

Hazrat

Zhou

2022

Cells

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Isthmin (ISM) is a secreted protein family with two members, namely ISM1 and ISM2, both containing a TSR1 domain followed by an AMOP domain. Its broad expression pattern suggests diverse functions in developmental and physiological processes. Over the past few years, multiple studies have focused on the functional analysis of the ISM protein family in several events, including angiogenesis, metabolism, organ homeostasis, immunity, craniofacial development, and cancer. Even though ISM was identified two decades ago, we are still short of understanding the roles of the ISM protein family in embryonic development and other pathological processes. To address the role of ISM, functional studies have begun but unresolved issues remain. To elucidate the regulatory mechanism of ISM, it is crucial to determine its interactions with other ligands and receptors that lead to the activation of downstream signalling pathways. This review provides a perspective on the gene organization and evolution of the ISM family, their links with developmental and physiological functions, and key questions for the future.

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

Cited by 4 publications

References 21 publications

Phosphoproteomic mapping reveals distinct signaling actions and activation of muscle protein synthesis by Isthmin-1

Phosphoproteomic mapping reveals distinct signaling actions and activation of muscle protein synthesis by Isthmin-1

Phosphoproteomic mapping reveals distinct signaling actions and activation of protein synthesis and muscle hypertrophy by Isthmin-1

Isthmin—A Multifaceted Protein Family

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