Intrinsic Site-Specific Differences in the Expression of Leptin in Human Adipocytes and Its Autocrine Effects on Glucose Uptake

Obesity-related insulin resistance is linked to a chronic state of systemic and adipose tissue-derived inflammation. Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone also acting on adipocytes. We investigated whether GIP affects inflammation, lipolysis, and insulin resistance in human adipocytes. Human subcutaneous preadipocyte-derived adipocytes, differentiated in vitro, were treated with human GIP to analyze mRNA expression and protein secretion of cytokines, glycerol, and free fatty acid release and insulin-induced glucose uptake. GIP induced mRNA expression of IL-6, IL-1β, and the IL-1 receptor antagonist IL-1Ra, whereas TNFα, IL-8, and monocyte chemotactic protein (MCP)-1 remained unchanged. Cytokine induction involved PKA and the NF-κB pathway as well as an autocrine IL-1 effect. Furthermore, GIP potentiated IL-6 and IL-1Ra secretion in the presence of LPS, IL-1β, and TNFα. GIP induced lipolysis via activation of hormone-sensitive lipase and was linked to NF-κB activation. Finally, chronic GIP treatment impaired insulin-induced glucose uptake possibly due to the observed impaired translocation of glucose transporter GLUT4. In conclusion, GIP induces an inflammatory and prolipolytic response via the PKA -NF-κB-IL-1 pathway and impairs insulin sensitivity of glucose uptake in human adipocytes.

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HMOX1 as a marker of iron excess-induced adipose tissue dysfunction, affecting glucose uptake and respiratory capacity in human adipocytes

Diabetologia ◽

10.1007/s00125-017-4228-0 ◽

2017 ◽

Vol 60 (5) ◽

pp. 915-926 ◽

Cited By ~ 11

Author(s):

José María Moreno-Navarrete ◽

Francisco Ortega ◽

Amaia Rodríguez ◽

Jèssica Latorre ◽

Sara Becerril ◽

...

Keyword(s):

Adipose Tissue ◽

Glucose Uptake ◽

Human Adipocytes ◽

Respiratory Capacity ◽

Adipose Tissue Dysfunction

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Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Enhance Insulin Sensitivity in Insulin Resistant Human Adipocytes

Current Medical Science ◽

10.1007/s11596-021-2323-4 ◽

2021 ◽

Vol 41 (1) ◽

pp. 87-93

Author(s):

Mei-ting Chen ◽

Yi-ting Zhao ◽

Li-yuan Zhou ◽

Ming Li ◽

Qian Zhang ◽

...

Keyword(s):

Insulin Resistance ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Insulin Sensitivity ◽

Glucose Uptake ◽

Umbilical Cord ◽

Sirtuin 1 ◽

Human Umbilical Cord ◽

Human Adipocytes ◽

Insulin Resistant

SummaryInsulin resistance is an essential characteristic of type 2 diabetes mellitus (T2DM), which can be induced by glucotoxicity and adipose chronic inflammation. Mesenchymal stem cells (MSCs) and their exosomes were reported to ameliorate T2DM and its complications by their immunoregulatory and healing abilities. Exosomes derived from MSCs contain abundant molecules to mediate crosstalk between cells and mimic biological function of MSCs. But the role of exosomes derived from human umbilical cord mesenchymal stem cells (hUC-MSCs) in insulin resistance of human adipocytes is unclear. In this study, exosomes were harvested from the conditioned medium of hUC-MSCs and added to insulin-resistant adipocytes. Insulin-stimulated glucose uptake was measured by glucose oxidase/peroxidase assay. The signal pathway involved in exosome-treated adipocytes was detected by RT-PCR and Western blotting. The biological characteristics and function were compared between hUC-MSCs and human adipose-derived mesenchymal stem cells (hAMSCs). The results showed that hAMSCs had better adipogenic ability than hUC-MSCs. After induction of mature adipocytes by adipogenesis of hAMSC, the model of insulin-resistant adipocytes was successfully established by TNF-α and high glucose intervention. After exosome treatment, the insulin-stimulated glucose uptake was significantly increased. In addition, the effect of exosomes could be stabilized for at least 48 h. Furthermore, the level of leptin was significantly decreased, and the mRNA expression of sirtuin-1 and insulin receptor substrate-1 was significantly upregulated after exosome treatment. In conclusion, exosomes significantly improve insulin sensitivity in insulin-resistant human adipocytes, and the mechanism involves the regulation of adipokines.

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Assessment of D-Glucose Uptake in Isolated Human Adipocytes

Hormone and Metabolic Research ◽

10.1055/s-2007-1009179 ◽

1989 ◽

Vol 21 (03) ◽

pp. 156-157 ◽

Cited By ~ 1

Author(s):

S. Zeuzem ◽

E. Jungmann ◽

T. Henne ◽

K. Schöffling

Keyword(s):

Glucose Uptake ◽

Human Adipocytes

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Exercise increases TBC1D1 phosphorylation in human skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00042.2011 ◽

2011 ◽

Vol 301 (1) ◽

pp. E164-E171 ◽

Cited By ~ 47

Author(s):

Niels Jessen ◽

Ding An ◽

Aina S. Lihn ◽

Jonas Nygren ◽

Michael F. Hirshman ◽

...

Keyword(s):

Skeletal Muscle ◽

Weight Loss ◽

Insulin Sensitivity ◽

Glucose Uptake ◽

Human Skeletal Muscle ◽

Dietary Intervention ◽

Rab Gtpase ◽

Site Specific ◽

Akt Phosphorylation ◽

Single Bout

Exercise and weight loss are cornerstones in the treatment and prevention of type 2 diabetes, and both interventions function to increase insulin sensitivity and glucose uptake into skeletal muscle. Studies in rodents demonstrate that the underlying mechanism for glucose uptake in muscle involves site-specific phosphorylation of the Rab-GTPase-activating proteins AS160 (TBC1D4) and TBC1D1. Multiple kinases, including Akt and AMPK, phosphorylate TBC1D1 and AS160 on distinct residues, regulating their activity and allowing for GLUT4 translocation. In contrast to extensive rodent-based studies, the regulation of AS160 and TBC1D1 in human skeletal muscle is not well understood. In this study, we determined the effects of dietary intervention and a single bout of exercise on TBC1D1 and AS160 site-specific phosphorylation in human skeletal muscle. Ten obese (BMI 33.4 ± 2.4, M-value 4.3 ± 0.5) subjects were studied at baseline and after a 2-wk dietary intervention. Muscle biopsies were obtained from the subjects in the resting (basal) state and immediately following a 30-min exercise bout (70% V̇o2 max). Muscle lysates were analyzed for AMPK activity and Akt phosphorylation and for TBC1D1 and AS160 phosphorylation on known or putative AMPK and Akt sites as follows: AS160 Ser711 (AMPK), TBC1D1 Ser231 (AMPK), TBC1D1 Ser660 (AMPK), TBC1D1 Ser700 (AMPK), and TBC1D1 Thr590 (Akt). The diet intervention that consisted of a major shift in the macronutrient composition resulted in a 4.2 ± 0.4 kg weight loss ( P < 0.001) and a significant increase in insulin sensitivity ( M value 5.6 ± 0.6), but surprisingly, there was no effect on expression or phosphorylation of any of the muscle-signaling proteins. Exercise increased muscle AMPKα2 activity but did not increase Akt phosphorylation. Exercise increased phosphorylation on AS160 Ser711, TBC1D1 Ser231, and TBC1D1 Ser660 but had no effect on TBC1D1 Ser700. Exercise did not increase TBC1D1 Thr590 phosphorylation or TBC1D1/AS160 PAS phosphorylation, consistent with the lack of Akt activation. These data demonstrate that a single bout of exercise regulates TBC1D1 and AS160 phosphorylation on multiple sites in human skeletal muscle.

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