Metabolic regulator LKB1 controls adipose tissue ILC2 PD-1 expression and mitochondrial homeostasis to prevent insulin resistance
Adipose tissue group 2 innate lymphoid cells (ILC2s) help maintain metabolic homeostasis by sustaining type 2 immunity and promoting adipose beiging. Although impairment of the ILC2 compartment contributes to obesity-associated insulin resistance, the underlying mechanisms have not been elucidated....
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Veröffentlicht in: | Immunity (Cambridge, Mass.) Mass.), 2024-06, Vol.57 (6), p.1289-1305.e9 |
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Sprache: | eng |
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Zusammenfassung: | Adipose tissue group 2 innate lymphoid cells (ILC2s) help maintain metabolic homeostasis by sustaining type 2 immunity and promoting adipose beiging. Although impairment of the ILC2 compartment contributes to obesity-associated insulin resistance, the underlying mechanisms have not been elucidated. Here, we found that ILC2s in obese mice and humans exhibited impaired liver kinase B1 (LKB1) activation. Genetic ablation of LKB1 disrupted ILC2 mitochondrial metabolism and suppressed ILC2 responses, resulting in exacerbated insulin resistance. Mechanistically, LKB1 deficiency induced aberrant PD-1 expression through activation of NFAT, which in turn enhanced mitophagy by suppressing Bcl-xL expression. Blockade of PD-1 restored the normal functions of ILC2s and reversed obesity-induced insulin resistance in mice. Collectively, these data present the LKB1-PD-1 axis as a promising therapeutic target for the treatment of metabolic disease.
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•LKB1 signaling is impaired in adipose tissue ILC2s from both mice and humans•LKB1 deficiency impairs ILC2 function and promotes obesity-associated insulin resistance•LKB1 sustains ILC2 mitochondrial and effector functions by inhibiting PD-1 expression•Targeting the LKB1-PD-1 axis may be a promising approach to metabolic disease therapy
Obesity induces ILC2 dysfunction in adipose tissue and insulin resistance by undetermined mechanisms. Here, Sun et al. show that liver kinase B1 (LKB1) signaling protects ILC2s from mitophagy by suppressing PD-1 expression. Moreover, PD-1 blockade restores ILC2 function and reverses obesity-associated insulin resistance. |
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ISSN: | 1074-7613 1097-4180 1097-4180 |
DOI: | 10.1016/j.immuni.2024.04.024 |