TY  - JOUR
A1  - Fayyaz, Susann
A1  - Japtok, Lukasz
A1  - Schumacher, Fabian
A1  - Wigger, Dominik
A1  - Schulz, Tim Julius
A1  - Haubold, Kathrin
A1  - Gulbins, Erich
A1  - Völler, Heinz
A1  - Kleuser, Burkhard
T1  - Lysophosphatidic acid inhibits insulin signaling in primary rat hepatocytes via the LPA(3) receptor subtype and is increased in obesity
JF  - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology
N2  - Background/Aims:
Obesity is a main risk factor for the development of hepatic insulin resistance and it is accompanied by adipocyte hypertrophy and an elevated expression of different adipokines such as autotaxin (ATX). ATX converts lysophosphatidylcholine to lysophosphatidic acid (LPA) and acts as the main producer of extracellular LPA. This bioactive lipid regulates a broad range of physiological and pathological responses by activation of LPA receptors (LPA1-6).
Methods:
The activation of phosphatidylinositide 3-kinases (PI3K) signaling (Akt and GSK-3ß) was analyzed via western blotting in primary rat hepatocytes. Incorporation of glucose into glycogen was measured by using radio labeled glucose. Real-time PCR analysis and pharmacological modulation of LPA receptors were performed. Human plasma LPA levels of obese (BMI > 30, n = 18) and normal weight individuals (BMI 18.5-25, n = 14) were analyzed by liquid chromatography tandem-mass spectrometry (LC-MS/MS).
Results:
Pretreatment of primary hepatocytes with LPA resulted in an inhibition of insulin-mediated Gck expression, PI3K activation and glycogen synthesis. Pharmacological approaches revealed that the LPA3-receptor subtype is responsible for the inhibitory effect of LPA on insulin signaling. Moreover, human plasma LPA concentrations (16: 0 LPA) of obese participants (BMI > 30) are significantly elevated in comparison to normal weight individuals (BMI 18.5-25).
Conclusion:
LPA is able to interrupt insulin signaling in primary rat hepatocytes via the LPA3 receptor subtype. Moreover, the bioactive lipid LPA (16: 0) is increased in obesity.
KW  - Lysophosphatidic acid
KW  - Insulin signaling
KW  - Adipose tissue
KW  - Autotaxin
KW  - Hepatic insulin resistance
KW  - LPA(3) receptor subtype
Y1  - 2017
U6  - https://doi.org/10.1159/000480470
SN  - 1015-8987
SN  - 1421-9778
VL  - 43
SP  - 445
EP  - 456
PB  - Karger
CY  - Basel
ER  - 
TY  - JOUR
A1  - Hauffe, Robert
A1  - Rath, Michaela
A1  - Schell, Mareike
A1  - Ritter, Katrin
A1  - Kappert, Kai
A1  - Deubel, Stefanie
A1  - Ott, Christiane
A1  - Jähnert, Markus
A1  - Jonas, Wenke
A1  - Schürmann, Annette
A1  - Kleinridders, André
T1  - HSP60 reduction protects against diet-induced obesity by modulating energy metabolism in adipose tissue
JF  - Molecular Metabolism
N2  - Objective
Insulin regulates mitochondrial function, thereby propagating an efficient metabolism. Conversely, diabetes and insulin resistance are linked to mitochondrial dysfunction with a decreased expression of the mitochondrial chaperone HSP60. The aim of this investigation was to determine the effect of a reduced HSP60 expression on the development of obesity and insulin resistance.

Methods
Control and heterozygous whole-body HSP60 knockout (Hsp60+/−) mice were fed a high-fat diet (HFD, 60% calories from fat) for 16 weeks and subjected to extensive metabolic phenotyping. To understand the effect of HSP60 on white adipose tissue, microarray analysis of gonadal WAT was performed, ex vivo experiments were performed, and a lentiviral knockdown of HSP60 in 3T3-L1 cells was conducted to gain detailed insights into the effect of reduced HSP60 levels on adipocyte homeostasis.

Results
Male Hsp60+/− mice exhibited lower body weight with lower fat mass. These mice exhibited improved insulin sensitivity compared to control, as assessed by Matsuda Index and HOMA-IR. Accordingly, insulin levels were significantly reduced in Hsp60+/− mice in a glucose tolerance test. However, Hsp60+/− mice exhibited an altered adipose tissue metabolism with elevated insulin-independent glucose uptake, adipocyte hyperplasia in the presence of mitochondrial dysfunction, altered autophagy, and local insulin resistance.

Conclusions
We discovered that the reduction of HSP60 in mice predominantly affects adipose tissue homeostasis, leading to beneficial alterations in body weight, body composition, and adipocyte morphology, albeit exhibiting local insulin resistance.
KW  - Mitochondria
KW  - Stress response
KW  - Obesity
KW  - Glucose homeostasis
KW  - Insulin resistance
KW  - Adipose tissue
Y1  - 2021
U6  - https://doi.org/10.1016/j.molmet.2021.101276
SN  - 2212-8778
VL  - 53
SP  - 1
EP  - 14
PB  - Elsevier
CY  - Amsterdam, Niederlande
ER  -