Zhengtang Qi1,2, Weina Liu3,4, Jie Xia1,2, Xiangli Xue1,2, Wenbin Liu1,2, Zhuochun Huang1,2, Xue Zhang1,2, Yong Zou1,2, Jianchao Liu1,2, Jiatong Liu1,2, Xingtian Li1,2, Lu Cao1,2, Lingxia Li1,2, Zhiming Cui1,2, Benlong Ji1,2, Qiang Zhang1,2, Shuzhe Ding5,6. 1. The Key Laboratory of Adolescent Health Assessment and Exercise Intervention (Ministry of Education), East China Normal University, Shanghai, 200241, China. 2. School of Physical Education and Health, East China Normal University, Shanghai, 200241, China. 3. The Key Laboratory of Adolescent Health Assessment and Exercise Intervention (Ministry of Education), East China Normal University, Shanghai, 200241, China. wnliu@tyxx.ecnu.edu.cn. 4. School of Physical Education and Health, East China Normal University, Shanghai, 200241, China. wnliu@tyxx.ecnu.edu.cn. 5. The Key Laboratory of Adolescent Health Assessment and Exercise Intervention (Ministry of Education), East China Normal University, Shanghai, 200241, China. szding@tyxx.ecnu.edu.cn. 6. School of Physical Education and Health, East China Normal University, Shanghai, 200241, China. szding@tyxx.ecnu.edu.cn.
Abstract
BACKGROUND: FAM132b (myonectin) has been identified as a muscle-derived myokine with exercise and has hormone activity in circulation to regulate iron homeostasis and lipid metabolism via unknown receptors. Here, we aim to explore the potential of adeno-associated virus to deliver FAM132b in vivo to develop a gene therapy against obesity. METHODS: Adeno-associated virus AAV9 were engineered to induce overexpression of FAM132b with two mutations, A136T and P159A. Then, AAV9 was delivered into high-fat diet mice through tail vein, and glucose homeostasis and obesity development of mice were observed. Methods of structural biology were used to predict the action site or receptor of the FAM132b mutant. RESULTS: Treatment of high-fat diet-fed mice with AAV9 improved glucose intolerance and insulin resistance, and resulted in reductions in body weight, fat depot, and adipocyte size. Codon-optimized FAM132b (coFAM132b) reduced the glycemic response to epinephrine (EPI) in the whole body and increased the lipolytic response to EPI in adipose tissues. However, FAM132b knockdown by shRNA significantly increased the glycemic response to EPI in vivo and reduced adipocyte response to EPI and adipose tissue browning. Structural analysis predicted that the FAM132b mutant with A136T and P159A may form a weak bond with β2 adrenergic receptor (ADRB2) and may have more affinity for insulin and insulin-receptor complexes. CONCLUSIONS: Our study underscores the potential of FAM132b gene therapy with codon optimization to treat obesity by modulating the adrenergic response and insulin action. Both structural biological analysis and in vivo experiments suggest that the adrenergic response and insulin action are most likely blockaded by FAM132b mutants.
BACKGROUND: FAM132b (myonectin) has been identified as a muscle-derived myokine with exercise and has hormone activity in circulation to regulate iron homeostasis and lipid metabolism via unknown receptors. Here, we aim to explore the potential of adeno-associated virus to deliver FAM132b in vivo to develop a gene therapy against obesity. METHODS: Adeno-associated virus AAV9 were engineered to induce overexpression of FAM132b with two mutations, A136T and P159A. Then, AAV9 was delivered into high-fat diet mice through tail vein, and glucose homeostasis and obesity development of mice were observed. Methods of structural biology were used to predict the action site or receptor of the FAM132b mutant. RESULTS: Treatment of high-fat diet-fed mice with AAV9 improved glucose intolerance and insulin resistance, and resulted in reductions in body weight, fat depot, and adipocyte size. Codon-optimized FAM132b (coFAM132b) reduced the glycemic response to epinephrine (EPI) in the whole body and increased the lipolytic response to EPI in adipose tissues. However, FAM132b knockdown by shRNA significantly increased the glycemic response to EPI in vivo and reduced adipocyte response to EPI and adipose tissue browning. Structural analysis predicted that the FAM132b mutant with A136T and P159A may form a weak bond with β2 adrenergic receptor (ADRB2) and may have more affinity for insulin and insulin-receptor complexes. CONCLUSIONS: Our study underscores the potential of FAM132b gene therapy with codon optimization to treat obesity by modulating the adrenergic response and insulin action. Both structural biological analysis and in vivo experiments suggest that the adrenergic response and insulin action are most likely blockaded by FAM132b mutants.
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