Chemerin, a secreted protein mainly produced by adipocytes and hepatocytes, plays a variety of roles in endocrine or paracrine signaling. As reported in human epidemiology, chemerin was correlated with osteoporosis. And the previous in vitro study found that chemerin knockdown promoted osteogenesis and inhibited adipogenesis. However, the function of chemerin in bone metabolism and the underlying mechanism remains unclear. In this study, we uncovered the in vivo function of chemerin in bone homeostasis. We discovered that in obese mice, chemerin was increased in serum, while decreased in the bone marrow; and the chemerin expression in bone tissue was positively correlated with osteogenic genes. To further investigate the function of chemerin in bone metabolism, we generated chemerin deficiency and overexpression mice. We found bone mass and osteogenesis were decreased in chemerin deficiency mice, while were increased in chemerin overexpression mice. Furthermore, we observed that the chemerin expression increased during osteogenic differentiation of MSCs. Besides, we verified that chemerin promoted osteogenic differentiation in C3H10T1/2 cells and BMSCs through Akt/Gsk3β/β‐catenin axis. Treatment with Akt inhibitor (MK2206) abolished the promoting effect of chemerin on osteogenic differentiation and active β‐catenin. Together, our results suggest chemerin in bone marrow, not in serum, promotes osteogenic differentiation and bone formation via Akt/Gsk3β/β‐catenin axis. Chemerin may serve as a therapeutic strategy for osteoporosis.

Islet transplantation is regarded as the most promising treatment for type 1 diabetes (T1D). However, the function of grafted islet could be damaged on account of transplant rejection and/or hypoxia several years later after transplantation. We proposed a hypothetical functionalized hydrogel model, which encapsulates sufficient A20 highexpressing islets and supporting cells, and performs as a drug release system releasing immunosuppressants and growth factors, to improve the outcome of pancreatic islet transplantation. Once injected in vivo, the hydrogel can gel and offer a robust mechanical structure for the A20 high-expressing islets and supporting cells. The natural biomaterials (eg, heparin) added into the hydrogel provide adhesive sites for islets to promote islets' survival. Furthermore, the hydrogel encapsulates various supporting cells, which can facilitate the vascularization and/or prevent the immune system attacking the islet graft. Based on the previous studies that generally applied one or two combined strategies to protect the function of islet graft, we designed this hypothetical multifunctional encapsulation hydrogel model with various functions. We hypothesized that the islet graft could survive and maintain its function for a longer time in vivo compared with naked islets. This hypothetical model has a limitation in terms of clinical application. Future development work will focus on verifying the function and safety of this hypothetical islet transplantation hydrogel model in vitro and in vivo.

Type 2 diabetes mellitus (T2DM) is associated with an increased risk of bone fracture, but the bone mineral density (BMD) is typically normal or higher in such patients. Because the fracture risk is independent of reduced BMD, bone fragility in T2DM may be partially due to poor bone quality. The mechanisms triggering bone quality abnormalities in T2DM are complex, and include the accumulation of advanced glycation end-products, the increased inflammation, and low bone turnover. Matrix metalloproteinases (MMPs) in bone can hydrolyze the bone matrix. Tissue inhibitors of MMPs (TIMPs) can inhibit the activity of MMPs. Both MMPs and TIMPs participate in mediating bone quality. Among all types of TIMPs, TIMP-1 is mostly reportedly increased in the serum of T2DM patients. Because osteocytes can express TIMP-1, and osteocyte pericellular matrix influences bone quality partially regulated by perilacunar/canalicular remodeling, we hypothesized that TIMP-1 at sites of osteocyte lacunar-canalicular system is involved in T2DM bone fragility.

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Obesity has become an extensive threat to human health due to associated chronic inflammation and metabolic diseases. Apoptosis-associated speck-like protein (ASC) is a critical link between inflammasome and apoptosis-inducing proteins. In this study, we aimed to clarify the role of ASC in lipid metabolism. With high-fat diet (HFD) and knockout leptin gene mice (ob/ob), we found that ASC expression in subcutaneous adipose tissue (SAT) correlated with obesity. It could also positively regulate the reprogramming of cellular energy metabolism. Stromal vascular fractions (SVF) cells derived from the SAT of Asc−/− mice or SVF from wild-type (WT) mice transfected with ASC siRNA were used to further investigate the underlying molecular mechanisms. We found ASC deficiency could lead to lipogenesis and inhibit lipolysis in SAT, aggravating lipid accumulation and impairing metabolic balance. In addition, our results showed that p53 and AMPKα expression were inhibited in SAT when ASC level was low. p53 and AMP-activated protein kinase α (AMPKα) were then assessed to elucidate whether they were downstream of ASC in regulating lipid metabolism. Our results revealed that ASC deficiency could promote lipid accumulation by increasing lipogenesis and decreasing lipolysis through p53/AMPKα axis. Regulation of ASC on lipid metabolism might be a novel therapeutic target for obesity.

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