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Targeting Kindlin-2 in adipocytes increases bone mass through inhibiting FAS/PPARγ/FABP4 signaling in mice
Wanze Tang1,2, Zhen Ding1, Huanqing Gao1
1Department of Biochemistry, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen 518055, China.
Abstract:
Osteoporosis (OP) is a systemic skeletal disease that primarily affects the elderly population, which greatly increases the risk of fractures. Here we report that Kindlin-2 expression in adipose tissue increases during aging and high-fat diet fed and is accompanied by decreased bone mass. Kindlin-2 specific deletion (K2KO) controlled by Adipoq-Cre mice or adipose tissue-targeting AAV (AAV-Rec2-CasRx-sgK2) significantly increases bone mass. Mechanistically, Kindlin-2 promotes peroxisome proliferator-activated receptor gamma (PPARγ) activation and downstream fatty acid binding protein 4 (FABP4) expression through stabilizing fatty acid synthase (FAS), and increased FABP4 inhibits insulin expression and decreases bone mass. Kindlin-2 inhibition results in accelerated FAS degradation, decreased PPARγ activation and FABP4 expression, and therefore increased insulin expression and bone mass. Interestingly, we find that FABP4 is increased while insulin is decreased in serum of OP patients. Increased FABP4 expression through PPARγ activation by rosiglitazone reverses the high bone mass phenotype of K2KO mice. Inhibition of FAS by C75 phenocopies the high bone mass phenotype of K2KO mice. Collectively, our study establishes a novel Kindlin-2/FAS/PPARγ/FABP4/insulin axis in adipose tissue modulating bone mass and strongly indicates that FAS and Kindlin-2 are new potential targets and C75 or AAV-Rec2-CasRx-sgK2 treatment are potential strategies for OP treatment.
Insights
Kindlin-2 in fat tissue promotes osteoporosis by increasing FABP4 and decreasing insulin. Inhibiting Kindlin-2 or fatty acid synthase (FAS) increases bone mass, offering potential osteoporosis treatments.
Area of Science:
- Endocrinology
- Bone Biology
- Metabolic Diseases
Background:
- Osteoporosis (OP) is a major health issue in the elderly, increasing fracture risk.
- Adipose tissue plays a role in bone metabolism.
- Kindlin-2 expression in adipose tissue increases with aging and high-fat diets, correlating with decreased bone mass.
Purpose of the Study:
- To investigate the role of Kindlin-2 in adipose tissue on bone mass regulation.
- To elucidate the molecular mechanisms linking Kindlin-2, adipose tissue, and bone metabolism.
- To identify potential therapeutic targets for osteoporosis.
Main Methods:
- Utilized Kindlin-2 specific deletion (K2KO) in mice using Adipoq-Cre and adipose tissue-targeting AAV (AAV-Rec2-CasRx-sgK2).
- Investigated the molecular pathways involving Kindlin-2, fatty acid synthase (FAS), peroxisome proliferator-activated receptor gamma (PPARγ), fatty acid binding protein 4 (FABP4), and insulin.
- Analyzed serum markers (FABP4, insulin) in osteoporosis patients.
- Administered rosiglitazone and C75 to modulate the identified pathways.
Main Results:
- Kindlin-2 deletion in adipose tissue significantly increased bone mass.
- Kindlin-2 stabilizes FAS, promoting PPARγ activation and FABP4 expression, which inhibits insulin and reduces bone mass.
- Kindlin-2 inhibition accelerated FAS degradation, decreased PPARγ/FABP4, and increased insulin, leading to higher bone mass.
- Increased serum FABP4 and decreased insulin were observed in osteoporosis patients.
- Rosiglitazone reversed the high bone mass phenotype in K2KO mice, while C75 mimicked it.
Conclusions:
- Established a novel Kindlin-2/FAS/PPARγ/FABP4/insulin axis in adipose tissue that modulates bone mass.
- Kindlin-2 and FAS are potential therapeutic targets for osteoporosis.
- C75 and AAV-Rec2-CasRx-sgK2 represent potential therapeutic strategies for osteoporosis treatment.
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