Visceral Adipose Tissue-directed Human Kallistatin Gene Therapy Improves Adipose Tissue Remodeling and Metabolic Health in Obese Mice

Abstract

Abstract Background: Adipose tissue remodeling is a dynamic process pathologically expedited in the obese state and related to obesity-associated disease progression closely. This study aimed to explore the effects of human kallistatin (HKS) on adipose tissue remodeling and obesity-related metabolic disorders in mice fed with a high-fat diet (HFD). Methods: Adenovirus-mediated HKS cDNA (Ad.HKS) and empty adenovirus (Ad.Null) were constructed and injected into the epididymal white adipose tissue (eWAT) of 8-week old male C57B/L mice. The mice were fed with normal or HFD for 28 days. The body weight and major lipid in circulation were then detected. Intraperitoneal glucose tolerance test (IGTT) and insulin tolerance test (ITT) were also performed. Oil-red O staining was used to assess the extent of lipid deposition in the liver. Immunohistochemistry and HE staining were used to measure HKS expression and adipose tissue morphology. Western blot and qRT-PCR were used to evaluate the expression of adipose function- related factors. Results: Compared with the Ad.Null group, HKS was highly expressed in serum and eWAT at the end of the experiment. Compared with Ad.Null mice, Ad.HKS mice had lower body weight and decreased serum and liver lipid levels after four weeks of HFD feeding. IGTT and ITT showed that HKS treatment maintained balanced glucose homeostasis. Additionally, inguinal white adipose tissue (iWAT) and eWAT in Ad.HKS mice contained more number of smaller size adipocytes and had less macrophage infiltration than Ad.Null group. HKS significantly increased the mRNA levels of adiponectin, vaspin, and eNOS. In contrast, HKS decreased RBP4 and TNFα levels in the adipose tissues. Western blot results showed that local injection of HKS significantly upregulated the protein expressions of SIRT1, p-AMPK, IRS1, p-AKT, and GLUT4 in eWAT. Conclusions: HKS injection in eWAT improves HFD-induced adipose tissue remodeling and function, thus significantly improving weight gain and dysregulation of glucose and lipid homeostasis in mice.