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Published on: May 19, 2023
Adipocyte STAT5 deficiency promotes adiposity and impairs lipid mobilisation in mice
Doris Kaltenecker1,2, Kristina M Mueller1,2, Pia Benedikt3
1Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
Aims/Hypothesis:
Dysfunction of lipid metabolism in white adipose tissue can substantially interfere with health and quality of life, for example in obesity and associated metabolic diseases. Therefore, it is important to characterise pathways that regulate lipid handling in adipocytes and determine how they affect metabolic homeostasis. Components of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway are involved in adipocyte physiology and pathophysiology. However, the exact physiological importance of the STAT family member STAT5 in white adipose tissue is yet to be determined. Here, we aimed to delineate adipocyte STAT5 functions in the context of lipid metabolism in white adipose tissue.
Methods:
We generated an adipocyte specific knockout of Stat5 in mice using the Adipoq-Cre recombinase transgene followed by in vivo and in vitro biochemical and molecular studies.
Results:
Adipocyte-specific deletion of Stat5 resulted in increased adiposity, while insulin resistance and gluconeogenic capacity was decreased, indicating that glucose metabolism can be improved by interfering with adipose STAT5 function. Basal lipolysis and fasting-induced lipid mobilisation were diminished upon STAT5 deficiency, which coincided with reduced levels of the rate-limiting lipase of triacylglycerol hydrolysis, adipose triglyceride lipase (ATGL, encoded by Pnpla2) and its coactivator comparative gene identification 58 (CGI-58). In a mechanistic analysis, we identified a functional STAT5 response element within the Pnpla2 promoter, indicating that Pnpla2 is transcriptionally regulated by STAT5.
Conclusions/Interpretation:
Our findings reveal an essential role for STAT5 in maintaining lipid homeostasis in white adipose tissue and provide a rationale for future studies into the potential of STAT5 manipulation to improve outcomes in metabolic diseases.
Insights
STAT5 in white adipose tissue is crucial for lipid metabolism. Its deficiency improves glucose metabolism but impairs lipid handling, suggesting STAT5 as a therapeutic target for metabolic diseases.
Area of Science:
- Adipose tissue biology
- Metabolic regulation
- Signal transduction pathways
Background:
- Dysfunctional lipid metabolism in white adipose tissue contributes to obesity and metabolic diseases.
- The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays a role in adipocyte function.
- The specific role of STAT5 in white adipose tissue lipid metabolism remains unclear.
Purpose of the Study:
- To investigate the function of STAT5 in adipocytes concerning lipid metabolism.
- To understand how STAT5 influences metabolic homeostasis in white adipose tissue.
Main Methods:
- Generation of adipocyte-specific Stat5 knockout mice using Adipoq-Cre.
- In vivo and in vitro biochemical and molecular analyses were performed.
Main Results:
- Adipocyte-specific Stat5 deletion led to increased adiposity but decreased insulin resistance and gluconeogenic capacity.
- STAT5 deficiency reduced basal lipolysis and fasting-induced lipid mobilization.
- Reduced levels of adipose triglyceride lipase (ATGL) and its coactivator CGI-58 were observed.
- A functional STAT5 response element in the Pnpla2 promoter indicated transcriptional regulation by STAT5.
Conclusions:
- STAT5 plays an essential role in maintaining lipid homeostasis in white adipose tissue.
- STAT5 manipulation could be a potential strategy for improving metabolic disease outcomes.
