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

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.

SUBMITTER: Buhler L

PROVIDER: S-EPMC7898469 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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

Bühler Lea L Maida Adriano A Vogl Elena Sophie ES Georgiadi Anastasia A Takacs Andrea A Kluth Oliver O Schürmann Annette A Feuchtinger Annette A von Toerne Christine C Tsokanos Foivos-Filippos FF Klepac Katarina K Wolff Gretchen G Sakurai Minako M Ekim Üstünel Bilgen B Nawroth Peter P Herzig Stephan S

Life science alliance 20210203 4

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 pro ...[more]

PMID: 33536239

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Project description:BackgroundObesity and its associated morbidities represent the major and most rapidly expanding world-wide health epidemic. Recent genome-wide association studies (GWAS) reveal that single nucleotide polymorphism (SNP) variant in the Family with Sequence Similarity 13, Member A (FAM13A) gene is strongly associated with waist-hip ratio (WHR) with adjustment for body mass index (BMI) (WHRadjBMI). However, the function of FAM13A in adipose development and obesity remains largely uncharacterized.MethodsThe expression of FAM13A in adipose tissue depots were investigated using lean, genetic obese and high fat diet-induced obese (DIO) animal models and during adipocyte differentiation. Stromal vascular cells (SVCs) or 3T3-L1 cells with gain and loss of function of FAM13A were used to determine the involvement of FAM13A in regulating adipocyte differentiation. Adipose development and metabolic homeostasis in Fam13a-/- mice were characterized under normal chow and high fat diet feeding.ResultsMurine FAM13A expression was nutritionally regulated and dramatically reduced in epididymal and subcutaneous fat in genetic and diet-induced obesity. Its expression was enriched in mature adipocytes and significantly upregulated during murine and human adipogenesis potentially through a peroxisome proliferator-activated receptor-gamma (PPARγ)-dependent mechanism. However, Fam13a-/- mice only exhibited a tendency of higher adiposity and were not protected from DIO and insulin resistance. While Fam13a-/- SVCs maintained normal adipogenesis, overexpression of FAM13A in 3T3-L1 preadipocytes downregulated β-catenin signaling and rendered preadipocytes more susceptible to apoptosis. Moreover, FAM13A overexpression largely blocked adipogenesis induced by a standard hormone cocktail, but adipogenesis can be partially rescued by the addition of PPARγ agonist pioglitazone at an early stage of differentiation.ConclusionsOur results suggest that FAM13A is dispensable for adipose development and insulin sensitivity. Yet the expression of FAM13A needs to be tightly controlled in adipose precursor cells for their proper survival and downstream adipogenesis. These data provide novel insights into the link between FAM13A and obesity.

Dataset Information

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

Publications

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

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