A negative feedback loop between TET2 and leptin in adipocyte regulates body weight

Area of Science:

• Epigenetics
• Metabolic disease
• Adipocyte biology

Background:

• Ten-eleven translocation (TET) 2 is crucial for epigenetic regulation via DNA demethylation.
• The role of TET2 in adipocytes, particularly during obesity, remains largely unexplored.

Purpose of the Study:

• To investigate the regulation and function of TET2 in adipocytes concerning obesity.
• To elucidate the relationship between leptin and TET2 in adipose tissue.

Main Methods:

• Investigated leptin's effect on adipocyte TET2 levels using JAK2-STAT3 signaling pathway analysis.
• Utilized adipocyte Tet2-deficient mice fed a high-fat diet to assess effects on weight gain and leptin sensitivity.
• Examined the interaction between TET2 and C/EBPα in regulating leptin gene expression.
• Analyzed TET2 levels in human adipocytes and correlated adipose TET2 with obesity and hyperleptinemia.

Main Results:

• Leptin was found to suppress adipocyte TET2 levels through JAK2-STAT3 signaling.
• Adipocyte-specific Tet2 deficiency protected against high-fat diet-induced weight gain and improved leptin sensitivity in mice.
• TET2 interacts with C/EBPα to promote leptin gene expression by increasing 5-hydroxymethylcytosine levels at the leptin promoter.
• Reduced adipose TET2 levels correlated with obesity-related hyperleptinemia in humans, and TET2 inhibition decreased leptin production in human adipocytes.

Conclusions:

• A negative feedback loop exists between TET2 and leptin in adipocytes.
• Adipocyte TET2 plays a significant role in regulating leptin production and energy homeostasis.
• These findings suggest a compensatory mechanism against obesity-induced metabolic dysfunction.