FATP2 at the crossroads of fatty acid transport, lipotoxicity, and complex disease
Paul N. Black, Concetta C. DiRusso
Paul N. Black, Concetta C. DiRusso
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Commentary

FATP2 at the crossroads of fatty acid transport, lipotoxicity, and complex disease

Abstract

Type 2 diabetes mellitus affects over 38 million Americans, with diabetic kidney disease as a major complication partly driven by lipotoxicity. Fatty acid transport protein 2 (FATP2) regulates uptake and activation of long-chain fatty acids, making it a therapeutic target in metabolic disease. In this issue of the JCI, Khan et al. investigated FATP2 in glycemic control. In db/db mice, global FATP2 deletion reduced plasma glucose via sustained insulin secretion, with expression restricted to pancreatic α cells. FATP2-deficient db/db mice also showed suppressed glucagon and reduced alanine-stimulated gluconeogenesis, implicating α cell FATP2 in systemic glucose regulation. The FATP2-specific inhibitor lipofermata enhanced α cell–derived glucagon-like peptide 1 (GLP-1) secretion, expanded GLP-1–positive α cell mass, and promoted paracrine insulin release — effects reversed by GLP-1 receptor antagonism. These findings identify FATP2 as a key regulator linking lipid handling to α cell hormone secretion and glucose control, positioning its inhibition as a potential complement to incretin-based therapies.

Authors

Paul N. Black, Concetta C. DiRusso

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Figure 1

FATP2 links lipid handling to GLP-1 secretion in a cells, with implications for glycemic control.

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FATP2 links lipid handling to GLP-1 secretion in a cells, with implicati...
(A) FATP2 mediates uptake of LCFAs and very LCFAs into α cells. Khan et al. studied its effects in diabetic db/db mice, which model the β cell loss and hyperglycemia associated with T2D (4). (B) Global deletion of Fatp2 in db/db mice led to α cell hypertrophy and increased GLP-1/GLP-1R signaling, which was associated with euglycemia. (C) Similarly, the FATP2-specific inhibitor lipofermata enhanced GLP-1 secretion in in vitro models, encouraging further investigation of FATP2 targeting as a complementary approach in diseases treated with incretin-based therapies.