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

Author(s):Show less -

Jiang, Zewen ^{[1, 2, 3]} ; Zhao, Meng ^{[1, 2, 3]} ; Voilquin, Laetitia ^{[1, 2, 3]} ; Jung, Yunshin ^{[1, 2, 3]} ; Aikio, Mari A. ^[4] ; Sahai, Tanushi ^{[1, 2, 3]} ; Dou, Florence Y. ^[4] ; Roche, Alexander M. ^[4] ; Carcamo-Orive, Ivan ^{[5, 2, 3, 6]} ; Knowles, Joshua W. ^{[5, 7, 2, 3, 6]} ; Wabitsch, Martin ^[8] ; Appel, Eric A. ^{[9, 2, 3, 10, 11]} ; Maikawa, Caitlin L. ^[10] ; Camporez, Joao Paulo ^{[12, 13]} ; Shulman, I, Gerald ; Tsai, Linus ^[14] ; Rosen, Evan D. ^[14] ; Gardner, Christopher D. ^[15] ; Spiegelman, Bruce M. ^[4] ; Svensson, Katrin J. ^{[1, 2, 3]}

Affiliation:Show less -

^[1] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 - USA

^[2] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 - USA

^[3] Stanford Univ, Sch Med, Stanford Diabet Res Ctr, Stanford, CA 94305 - USA

^[4] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 - USA

^[5] Stanford Univ, Sch Med, Cardiovasc Inst, Stanford, CA 94305 - USA

^[6] Stanford Univ, Sch Med, Div Cardiovasc Med, Dept Med, Stanford, CA 94305 - USA

^[7] Stanford Univ, Stanford Prevent Res Ctr, Stanford, CA 94305 - USA

^[8] Univ Med Ctr Ulm, Div Pediat Endocrinol & Diabet, Ulm - Germany

^[9] Stanford Univ, Dept Mat Sci & Engn, Stanford, CA 94305 - USA

^[10] Stanford Univ, Dept Bioengn, Stanford, CA 94305 - USA

^[11] Stanford Univ, Dept Pediat Endocrinol, Stanford, CA 94305 - USA

^[12] Univ Sao Paulo, Ribeirao Preto Sch Med, Dept Physiol, Sao Paulo - Brazil

^[13] I, Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06519 - USA

^[14] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Div Endocrinol Diabet & Metab, Boston, MA 02115 - USA

^[15] Stanford Univ, Stanford, CA 94305 - USA

• Document type: Journal article
• Source: Cell Metabolism; v. 33, n. 9, p. 1836+, SEP 7 2021.
• Web of Science Citations: 1

Abstract

With the increasing prevalence of type 2 diabetes and fatty liver disease, there is still an unmet need to better treat hyperglycemia and hyperlipidemia. Here, we identify isthmin-1 (Ism1) as an adipokine and one that has a dual role in increasing adipose glucose uptake while suppressing hepatic lipid synthesis. Ism1 ablation results in impaired glucose tolerance, reduced adipose glucose uptake, and reduced insulin sensitivity, demonstrating an endogenous function for Ism1 in glucose regulation. Mechanistically, Ism1 activates a PI3K-AKT signaling pathway independently of the insulin and insulin-like growth factor receptors. Notably, while the glucoregulatory function is shared with insulin, Ism1 counteracts lipid accumulation in the liver by switching hepatocytes from a lipogenic to a protein synthesis state. Furthermore, therapeutic dosing of recombinant Ism1 improves diabetes in diet-induced obese mice and ameliorates hepatic steatosis in a diet-induced fatty liver mouse model. These findings uncover an unexpected, bioactive protein hormone that might have simultaneous therapeutic potential for diabetes and fatty liver disease. (AU)

• FAPESP's process: 18/04956-5 - Impact of the estrogen receptor alpha on Non-Alcoholic Fatty Liver Disease and energetic metabolism of the liver
• Grantee: João Paulo Gabriel Camporez
• Support Opportunities: Research Grants - Young Investigators Grants