New players in high fat diet-induced obesity: LETM1 and CTMP
Jisoo Park1, Yuwen Li2, Seon-Hwan Kim3
1Metabolic Disease Institute, University of Cincinnati, Cincinnati, OH 45437, USA; Department of Pharmacology, Metabolic Diseases and Cell Signaling Laboratory, Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon 301-131, South Korea.
Objective:
Obesity contributes to insulin resistance and is a risk factor for diabetes. C-terminal modulator protein (CTMP) and leucine zipper/EF-hand-containing transmembrane protein 1 (LETM1) have been reported to influence the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB) signaling pathway via the modulation of PKB activity, a key player for insulin signaling. However, it remains unclear whether CTMP and LETM1 are associated with PI3K/PKB signaling in mouse models of obesity.
Materials/Methods:
To address this question, we used two different mouse models of obesity, including high-fat diet (HFD)-induced diabetic mice and genetically modified obese mice (ob/ob mice). The levels of insulin-signaling molecules in these mice were determined by immunohistochemical and Western blot analyses. The involvement of CTMP and LETM1 in PI3K/PKB signaling was investigated in HEK293 cells by transient transfection and adenovirus-mediated infection.
Results:
We found that the levels of insulin receptor, phosphorylated PKB, and LETM1 were lower and the level of CTMP was higher in the adipose tissue of obese mice on an HFD compared to lean mice on a chow diet. Similar results were obtained in ob/ob mice. In HEK293 cells, the activation of PKB increased the LETM1 level, and inhibition of PKB increased the CTMP level. The overexpression of CTMP suppressed the insulin-induced increase in PKB phosphorylation, which was abrogated by co-overexpression with LETM1.
Conclusion:
These results suggest that CTMP and LETM1 may participate in impaired insulin signaling in the adipose tissue of obese mice, raising the possibility that these parameters may serve as new candidate biomarkers or targets in the development of new therapeutic approaches for diabetes.
Insights
Obesity impairs insulin signaling. C-terminal modulator protein (CTMP) levels increase while leucine zipper/EF-hand-containing transmembrane protein 1 (LETM1) levels decrease in obese mice, suggesting roles in diabetes development.
Area of Science:
- Metabolic research
- Molecular biology
- Endocrinology
Background:
- Obesity is a major risk factor for type 2 diabetes, often linked to insulin resistance.
- The phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB) pathway is crucial for insulin signaling.
- C-terminal modulator protein (CTMP) and leucine zipper/EF-hand-containing transmembrane protein 1 (LETM1) are implicated in modulating PKB activity.
Purpose of the Study:
- To investigate the association between CTMP, LETM1, and PI3K/PKB signaling in obesity-induced diabetes models.
- To determine the roles of CTMP and LETM1 in the context of impaired insulin signaling in adipose tissue.
Main Methods:
- Utilized high-fat diet (HFD)-induced diabetic mice and genetically obese (ob/ob) mice.
- Analyzed insulin-signaling molecules using immunohistochemistry and Western blot.
- Investigated CTMP and LETM1 involvement in PI3K/PKB signaling in HEK293 cells via transfection and adenovirus infection.
Main Results:
- Obese mice exhibited lower levels of phosphorylated PKB and LETM1, and higher CTMP levels in adipose tissue compared to lean controls.
- PKB activation increased LETM1 levels, while PKB inhibition elevated CTMP levels in HEK293 cells.
- CTMP overexpression inhibited insulin-induced PKB phosphorylation, an effect reversed by co-overexpressing LETM1.
Conclusions:
- CTMP and LETM1 are implicated in the impaired insulin signaling observed in the adipose tissue of obese mice.
- These proteins represent potential novel biomarkers or therapeutic targets for managing diabetes associated with obesity.
