Lipocalin 13 enhances insulin secretion but is dispensable for systemic metabolic control.

Lea Bühler,Foivos-Filippos Tsokanos,Christine Von Toerne,Peter Nawroth,Bilgen Ekim Üstünel,Anastasia Georgiadi,Minako Sakurai,Adriano Maida,Oliver Kluth,Katarina Klepac,Gretchen Wolff,Stephan Herzig,Annette Schürmann,Annette Feuchtinger,Elena Sophie Vogl,Andrea Takacs

doi:10.26508/lsa.202000898

Abstract

Members of the lipocalin protein family serve as biomarkers for kidney disease and acute phase inflammatory reactions, and are under preclinical development for the diagnosis and therapy of allergies. However, none of the lipocalin family members has made the step into clinical development, mostly due to their complex biological activity and the lack of in-depth mechanistic knowledge. Here, we show that the hepatokine lipocalin 13 (LCN13) triggers glucose-dependent insulin secretion and cell proliferation of primary mouse islets. However, inhibition of endogenous LCN13 expression in lean mice did not alter glucose and lipid homeostasis. Enhanced hepatic secretion of LCN13 in either diet-induced or genetic obesity led to no discernible impact on systemic glucose and lipid metabolism, neither in preventive nor therapeutic setting. Of note, loss or forced LCN13 hepatic secretion did not trigger any compensatory regulation of related lipocalin family members. Together, these data are in stark contrast to the suggested gluco-regulatory and therapeutic role of LCN13 in obesity, and imply complex regulatory steps in LCN13 biology at the organismic level mitigating its principal insulinotropic effects.

Highlights

Systemic energy homeostasis critically depends on the tightly controlled interaction between the central nervous system and peripheral organs
To initially investigate the effects of lipocalin 13 (LCN13) on β-cell function, we used the murine pancreatic β-cell line MIN6, which expresses a potential receptor for lipocalin family members (Blache et al, 1998)
To guarantee optimal insulin secretion capacity, MIN6 cells were grown as pseudo-islets and used for experiments after reaching a size similar to primary mouse islets (Fig 1A; Hauge-Evans et al, 1999)

Summary

Introduction

Systemic energy homeostasis critically depends on the tightly controlled interaction between the central nervous system and peripheral organs. As an important metabolic organ, the liver coordinates multiple aspects of systemic glucose, lipid, and protein metabolism, including the body’s adaptation to the daily fasting–feeding cycle In this respect, numerous liver-secreted factors, the so-called hepatokines, have been identified with both biomarker as well as regulatory functions in systemic energy homeostasis. Numerous liver-secreted factors, the so-called hepatokines, have been identified with both biomarker as well as regulatory functions in systemic energy homeostasis This is exemplified by fetuin A, the circulating levels of which tightly correlate with obesity, diabetes, and other components of the metabolic syndrome in human cohorts (Ix et al, 2006; Stefan et al, 2008; Haukeland et al, 2012; Stefan & Haring, 2013)

Methods

Results

Conclusion