The Role of Sirtuins in Obesity and Osteoporosis and Their Therapeutic Potential

Academic Background

Obesity and osteoporosis (OP) are increasingly severe public health issues worldwide. Obesity is not only closely related to metabolic diseases such as cardiovascular diseases and diabetes but also has a complex association with the occurrence of osteoporosis. In recent years, Sirtuins (silent information regulators), as a class of NAD+-dependent histone deacetylases, have garnered significant attention in the fields of aging and endocrine metabolism. Sirtuins are believed to play an important role in the development of obesity and osteoporosis by regulating energy balance, lipid metabolism, and bone metabolism. However, no study has comprehensively explored the relationship between Sirtuins, obesity, and osteoporosis. Therefore, this paper aims to systematically elucidate the mechanisms of Sirtuins in obesity and osteoporosis and to explore the potential of targeting Sirtuins for the treatment of osteoporosis caused by obesity.

Source of the Paper

This paper was co-authored by Yikuan Du, Yuying Huo, and others, affiliated with the Tenth Affiliated Hospital of Southern Medical University, Dongguan Affiliated Hospital of Guangdong Medical University, and other institutions. The paper was published in 2025 in the journal Cell Communication and Signaling, titled Role of Sirtuins in Obesity and Osteoporosis: Molecular Mechanisms and Therapeutic Targets.

Main Content of the Paper

1. Mechanisms of Sirtuins in Obesity

Sirtuins regulate the occurrence and development of obesity through multiple mechanisms. Sirt1, Sirt3, Sirt6, and Sirt7 inhibit adipogenesis through different pathways. For example, Sirt1 inhibits adipocyte differentiation by upregulating the PI3K/Akt signaling pathway and suppressing the transcriptional activity of PPARγ. Sirt3 improves obesity by regulating mitochondrial energy homeostasis and promoting ATP production. Sirt6 inhibits adipogenesis by regulating glucose metabolism and insulin signaling pathways. Sirt7 indirectly affects adipogenesis by regulating the autoactivation of Sirt1.

Additionally, Sirtuins ameliorate obesity by promoting the “browning” of white adipose tissue and increasing the thermogenesis of brown adipose tissue. Sirt1 promotes the transformation of white adipose tissue into brown adipose tissue by deacetylating PPARγ, thereby increasing energy expenditure. Sirt5 maintains mitochondrial function and energy homeostasis by regulating protein succinylation and malonylation in brown adipose tissue.

2. Mechanisms of Sirtuins in Osteoporosis

The role of Sirtuins in osteoporosis is mainly reflected in promoting bone formation and inhibiting bone resorption. Sirt1 promotes osteoblast differentiation and bone formation by activating the Wnt signaling pathway. Sirt2 reduces osteoclast differentiation and bone resorption by inhibiting the NF-κB signaling pathway. Sirt3 promotes osteoblast differentiation and mitochondrial function by alleviating oxidative stress. Sirt6 maintains bone homeostasis by regulating the balance between bone formation and bone resorption. Sirt7 promotes osteoblast differentiation by deacetylating OSX (Osterix).

3. Potential Therapeutic Role of Sirtuins in Osteoporosis Induced by Obesity

Obesity and osteoporosis share many common pathogenic mechanisms, including genetic factors, environmental factors, endocrine hormone secretion, mesenchymal stem cells (MSCs), and insulin resistance. Sirtuins may play an important role in treating osteoporosis caused by obesity by regulating these common factors. For example, Sirt1 maintains the balance between bone and adipose tissue by regulating the osteogenic and adipogenic differentiation of MSCs. Sirt6 reduces osteoclast differentiation and bone resorption by inhibiting the NF-κB signaling pathway.

4. Potential of Sirtuins in Polyphenolic Natural Products for Treating Obesity and Osteoporosis

Polyphenolic natural products such as resveratrol and apple polyphenols show potential in combating obesity and osteoporosis by activating Sirt1. For example, resveratrol promotes the browning of white adipose tissue and bone formation by activating Sirt1. Apple polyphenols improve obesity and osteoporosis induced by a high-fat diet by regulating the Sirt1 signaling pathway.

Significance and Value of the Paper

This paper systematically elucidates the mechanisms of Sirtuins in obesity and osteoporosis and explores the potential of targeting Sirtuins for the treatment of osteoporosis caused by obesity. The research not only provides new perspectives for understanding the role of Sirtuins in metabolic diseases but also offers a theoretical basis for developing new therapeutic strategies. In particular, the application of Sirtuins in polyphenolic natural products provides new insights for the treatment of obesity and osteoporosis.

Highlights

1. Comprehensiveness: This paper is the first to systematically explore the relationship between Sirtuins, obesity, and osteoporosis, filling a research gap in this field.
2. Innovation: It proposes a new strategy for treating osteoporosis caused by obesity by targeting Sirtuins, which has significant clinical application value.
3. Interdisciplinary Approach: It integrates research findings from multiple disciplines, including metabolism, bone biology, and natural product chemistry, demonstrating the broad role of Sirtuins in various diseases.

Conclusion

Sirtuins play a key role in the development of obesity and osteoporosis. By regulating energy metabolism, adipogenesis, and bone metabolism, Sirtuins provide new targets for the treatment of obesity and osteoporosis. Future research should further explore the specific mechanisms of Sirtuins in different diseases and develop novel therapeutic approaches based on Sirtuins.