瘦素促进减肥,Sh2b1敲除小鼠 z-bo 2020-10-22 325

　　Leptin is a protein hormone secreted by adipose tissue, which can stimulate the sympathetic nervous system (SNS), promote energy expenditure and reduce weight, but the underlying molecular mechanism is still unclear. Recently, a research team led by Professor Liangyou Rui from the University of Michigan in the United States unveiled the key mechanism of leptin to promote weight loss.

　　They found that Sh2b1 in neurons expressing leptin receptor (LepR) can promote the stimulation of the sympathetic nervous system, which sends signals to brown fat to activate it, thereby maintaining weight and metabolism. This result was published in "Nature Communications" magazine.

　　Leptin is a key regulator of body weight and metabolism. The destruction of leptin/leptin receptor signaling often leads to morbid obesity and severe metabolic diseases. This signaling pathway is regulated by the tyrosine kinase JAK2. The research team previously discovered that the JAK2 binding protein Sh2b1 is a potent regulator of JAK2. It binds to JAK2 through the SH2 domain and greatly enhances JAK2 kinase activity.

　　Previous studies have found that restoring Sh2b1 expression in neurons can reverse the obesity phenotype of Sh2b1-null mice, indicating that neurons mediate the effects of Sh2b1 on body weight and metabolism. Therefore, the researchers hypothesized that Sh2b1 may directly regulate the leptin signaling pathway to enhance the ability of LepR neurons to control metabolism and weight.

　　Sh2b1 deletion causes obesity, insulin resistance and liver steatosis

　　To determine the role of Sh2b1 in leptin receptor neurons, the researchers constructed LepR cell-specific Sh2b1 knockout (Sh2b1ΔLepR) mice. They found that compared with control mice, Sh2b1ΔLepR male and female mice were heavier and had a significantly higher fat content, and the body temperature of Sh2b1ΔLepR mice was significantly lower, indicating that Sh2b1 in LepR neurons is important for maintaining body weight and body temperature. All are essential.

　　At the same time, they also assessed the insulin sensitivity and liver lipid content of Sh2b1ΔLepR mice. The results showed that compared with control mice, Sh2b1ΔLepR mice had significantly higher blood sugar levels and developed severe liver steatosis. Therefore, Sh2b1 in LepR neurons can help fight insulin resistance, type 2 diabetes and non-alcoholic fatty liver (NAFLD).

　　In order to distinguish whether the effects of Sh2b1 on body weight and metabolism are dependent on brain development, they constructed adult-onset hypothalamic-specific Sh2b1 knockout mice (Sh2b1-Cre mice were constructed by Saiye Biotech). They found that the hypothalamus-specific Sh2b1 knockout resulted in a significant increase in body weight and fat content in mice. Like Sh2b1ΔLepR mice, these mice also developed insulin resistance and severe liver steatosis. These data indicate that the regulation of body weight and metabolism by Sh2b1 in the hypothalamus has nothing to do with its effect on brain development.

　　After, the researchers constructed another mouse model, that is, mice overexpressing human SH2B1 in the hypothalamus, and fed the mice a high-fat diet to induce obesity. Compared with control mice, the body weight and fat content of overexpressing SH2B1 mice were significantly reduced. Moreover, SH2B1 specific overexpression greatly improved insulin resistance induced by high-fat diet and blocked liver steatosis. These data confirm that the hypothalamus Sh2b1 can prevent obesity, type 2 diabetes and NAFLD.

　　LepR neuron Sh2b1 is a key component of SNS/BAT/heat production axis

　　Next, the researchers evaluated the effect of hypothalamus Sh2b1 on brown fat (BAT) activity. They found that the loss of Sh2b1 resulted in albino of brown tissue and a significant down-regulation of the marker Ucp1. Ucp1 protein and mRNA were almost undetectable in Sh2b1ΔLepR mice at 22 weeks of age. Compared with control mice, Sh2b1ΔLepR mice have much lower body temperature after cold exposure. This indicates that the Sh2b1/BAT axis strictly regulates adaptive heat production and body temperature.

　　Considering the key role of the sympathetic nervous system (SNS) in the activation of brown fat, the researchers evaluated the impact of Sh2b1 deficiency on the sympathetic nerve transmission stimulated by leptin. Compared with control mice, the sympathetic nerve activity of Sh2b1ΔLepR mice was significantly reduced. Surprisingly, the absence of Sh2b1 in LepR neurons eliminated the ability of leptin to stimulate sympathetic nerve activity. Thus, leptin stimulation of sympathetic nerves requires the Sh2b1 branch of the LepR signaling pathway.

　　Next, they further studied the neuronal activity in the central sympathetic network. Cold exposure rapidly and powerfully increased the number of c-Fos neurons in Sh2b1f/f mice. For Sh2b1ΔLepR mice, the lack of Sh2b1 actually inhibited the activation of cold-stimulated neurons in the preoptic area and hypothalamus. Together, these results reveal a Sh2b1/SNS/BAT/heat production axis.

　　All in all, this study revealed that a LepR neuron Sh2b1/SNS/BAT/thermogenesis axis can fight obesity, type 2 diabetes and non-alcoholic fatty liver. LepR neuron Sh2b1 mediates the stimulation of the sympathetic nerve by leptin and supports the maintenance of the fatty sympathetic nervous system. In the future, Sh2b1/SNS/fat axis is expected to be a therapeutic target for the treatment of obesity and metabolic diseases.