Study Of LKB1 In Central Nervous System On Energy Balance

With the improvement of living conditions and changes in lifestyle,the number of obese people is increasing year by year.Obesity is associated with a variety of diseases,including heart type 2-diabetes,vascular disease,fatty liver,and tumors,which seriously threaten human health.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,this study intends to explore the effects and mechanisms of LKB1 on hypothalamic inflammation and DIO through tissue-specific knockout or overexpression of LKB1,and provide new theoretical support for the pathogenesis and prevention of obesity.Methods1.Eight-week-old male PomcLkb1 KO mice and control mice were fed standard diet(CFD)or high fat diet(HFD)for 12 weeks.Monitor food intake and weight regularly.Glucose tolerance and insulin tolerance were measured at the 11 th week of the experimental period.In the 12 th week of the experiment cycle,the body fat was measured by dual-energy X-ray absorption method.Then,we studied it at the physiological,morphological,and molecular biology levels.2.Adult male C57BL/6J mice(7–8 week old,22–24g)were purchased from Beijing Weitong-Lihua(Beijing,China).For the characterization of the experimental model,the mice were divided randomly into two groups:(1)chow-fat group,fed with chow diet;(2)high-fat group,fed with a high-fat diet.Body weight was recorded weekly.Food intake was measured daily.After feeding for 12 weeks,serum,adipose tissue,liver,and hypothalamus were collected at the end of the study.In order to overexpress the LKB1 experiment,the mice were randomly divided into three groups:(a)CF-AAV,fed with standard laboratory chow;(b)HF-AAV,fed with a high-fat diet;(c)HF-AAV-LKB1,fed with a high-fat diet.Next,we used the same experimental method above to evaluate the changes in body weight,food intake,hypothalamic inflammation indicators,and glucose and lipid metabolism of experimental mice.Results1.PomcLkb1 KO mice did not exhibit impairments under normal physiological conditions.After HFD intervention,the metabolic phenotype of the PomcLkb1 KO mice changed,manifesting as increased food intake and an enhanced obesity phenotype.More seriously,PomcLkb1 KO mice showed increased leptin resistance,worsened hypothalamic inflammation and reduced POMC neuronal expression.2.DIO mice had impaired LKB1 signaling in hypothalamus and worsened hypothalamic inflammation.Up-regulation of LKB1 expression in the hypothalamus inhibits food intake and weight gain;at the same time,overexpression of LKB1 in the hypothalamus increases insulin sensitivity and improves systemic lipid metabolism,thereby reducing liver fat accumulation and serum lipid levels.In addition,the overexpression of LKB1 in the hypothalamus significantly down-regulates the expression of inflammatory cytokines and the activation of NF-κB.Conclusions1.We provide evidence that LKB1 in POMC neurons plays a significant role in regulating energy homeostasis.LKB1 in POMC neurons emerges as a target for therapeutic intervention against HFD-induced obesity and metabolic diseases.2.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.