LKB1 up-regulation inhibits hypothalamic inflammation and attenuates diet-induced obesity in mice

Background: Diet-induced obesity (DIO) is associated with chronic, low-grade inflammation in the hypothalamus. The inflammatory pathway of the hypothalamus is activated during obesity, and inhibition of activation of the inflammatory pathway can partially reverse obesity. Therefore, exploring new targets for inhibiting hypothalamic inflammation will provide new ideas for the prevention and treatment of obesity. Liver kinase B1 (LKB1), a serine/threonine kinase, is a tumor suppressor and metabolic regulator. Recent studies have shown that LKB1 has a certain anti-inflammatory effect. However, a role of LKB1 in the regulation of hypothalamic inflammation remains unclear. Therefore, we examined whether LKB1 overexpression in the hypothalamus could weaken the hypothalamic inflammation and inhibit the development of obesity. Methods: LKB1 overexpressing adeno-associated virus (AAV) particles were injected stereotactically into the third ventricle (3 V) of C57BL/6 mice fed with HFD. We assessed changes in body mass and adiposity, food intake, hypothalamic inflammatory markers, and energy and glucose metabolism. Results: LKB1 up-regulation in hypothalamus attenuated diet-induced hypothalamic inflammation, reduced food intake and body weight gain. In addition, the overexpression of hypothalamic LKB1 increased the insulin sensitivity and improved whole-body lipid metabolism, which attenuated hepatic fat accumulation and serum lipid levels. Conclusion: Hypothalamic LKB1 up-regulation attenuates hypothalamic inflammation, and protects against hypothalamic inflammation induced damage to melanocortin system, resulting in lower food intake and lower fat mass accumulation, which consequently protects mice from the development of obesity. Our data suggest LKB1 as a novel negative regulator of hypothalamic inflammation, and also a potentially important target for treating other inflammatory diseases. (C) 2020 Elsevier Inc. All rights reserved.

Automated summary

Diet-induced obesity is associated with chronic inflammation in the hypothalamus. Overexpression of LKB1 in hypothalamus can attenuate inflammation, reduce food intake and weight gain, improve lipid metabolism, and decrease hepatic fat accumulation. This suggests LKB1 as a potential target for treating obesity and other inflammatory diseases.