Inhibition of dipeptidyl peptidase 8/9 impairs preadipocyte differentiation

Area of Science:

• Cell Biology
• Biochemistry
• Metabolic Diseases

Background:

• Adipocytes are central to adipose tissue function, and their dysfunction is linked to obesity and diabetes.
• The dipeptidyl peptidase (DPP) 4 family, including DPP4, DPP8, DPP9, and FAP, has known roles in metabolic regulation.
• The specific involvement of DPP8 and DPP9 in adipocyte differentiation remains largely unexplored.

Purpose of the Study:

• To investigate the role of DPP family enzymes, particularly DPP8 and DPP9, in adipogenesis.
• To determine the impact of DPP8/9 inhibition on preadipocyte differentiation and identify underlying molecular mechanisms.

Main Methods:

• Utilized a selective DPP8/9 inhibitor (1G244) and gene knockdown techniques in 3T3-L1 and 3T3-F422A preadipocytes.
• Assessed adipogenic differentiation and measured the expression of key regulators like PPARγ2.
• Investigated rescue effects using PPARγ agonists (TZDs) and PPARγ2 overexpression.

Main Results:

• Selective inhibition of DPP8/9, but not DPP4 or FAP, significantly blocked adipogenesis in preadipocytes.
• Knockdown of DPP8 or DPP9 impaired adipocyte differentiation.
• DPP8/9 inhibition reduced PPARγ2 induction, a critical factor in adipogenesis.
• Thiazolidinediones (TZDs) or PPARγ2 overexpression rescued the adipogenic defect caused by DPP8/9 inhibition.

Conclusions:

• DPP8 and DPP9 play a critical and previously unrecognized role in adipogenesis.
• The mechanism involves the regulation of PPARγ2 during preadipocyte differentiation.
• Targeting DPP8/9 may offer novel therapeutic strategies for metabolic disorders associated with adipocyte dysfunction.