Inhibition of CXXC5 function reverses obesity‐related metabolic diseases

Abstract

Background Metabolic diseases, including type 2 diabetes, have long been considered incurable, chronic conditions resulting from a variety of pathological conditions in obese patients. Growing evidence suggests the Wnt/β‐catenin pathway is a major pathway in adipose tissue remodelling, pancreatic β‐cell regeneration and energy expenditure through regulation of key metabolic target genes in various tissues. CXXC5‐type zinc finger protein 5 (CXXC5) is identified negative feedback regulator of the Wnt/β‐catenin pathway that functions via Dishevelled (Dvl) binding. Methods Expression level of CXXC5 was characterised in clinical samples and diabetes‐induced mice model. Diabetes‐induced mice model was established by using high‐fat diet (HFD). HFD‐fed mice treated with KY19334, a small molecule inhibiting CXXC5‐Dvl protein–protein interaction (PPI), was used to assess the role of CXXC5 in metabolic diseases. Results Here, we show that CXXC5 is overexpressed with suppression of Wnt/β‐catenin signalling in visceral adipose tissues of patients with obesity‐related diabetes. Meanwhile, Cxxc5 −/− mice fed an HFD exhibited resistance to metabolic dysregulation. KY19334 restores the lowered Wnt/β‐catenin signalling and reverses metabolic abnormalities as observed in HFD‐fed Cxxc5 −/− mice. Administration of KY19334 on HFD‐fed mice had a long‐lasting glucose‐controlling effect through remodelling of adipocytes and regeneration of pancreatic β‐cells. Conclusion Overall, the inhibition of CXXC5 function by small molecule‐mediated interference of Dvl binding is a potential therapeutic strategy for the treatment of obesity‐related diabetes.

Signaling pathways in obesity: mechanisms and therapeutic interventions

“…Inhibition of CXXC-type zinc-finger protein 5 (CXXC5), a negative feedback regulator of Wnt signaling, alleviates the phenotype of obesity-related diabetes. 255 Wnt signaling induces the synthesis of incretins within the small intestinal epithelium and is linked to T2D. 256 In addition, Wnt5a, a part of the noncanonical Wnt pathway, has been proven to induce obesity-associated inflammation in WAT and contribute to dysregulation in glucose metabolism in a JNK-dependent manner.…”

Blockade of CXXC5-dishevelled interaction inhibits adipogenic differentiation, obesity, and insulin resistance in mice

“…Body weight and food intake were measured once a week during the study. Assessment of fasting glucose levels, glucose tolerance test (GTT) and insulin tolerance test (ITT) were described in a previous study 17 . All mice were maintained under temperature and light-controlled (standard 12 h light/dark cycle) conditions and provided with food and water ad libitum.…”

“…Total blood of mice was collected by cardiac puncture after fasting. The blood was allowed to clot for 30 min and was then centrifuged for 10 min at 1000× g to obtain supernatant to measure metabolic parameters 17 . ELISA assay kits were used to assess serum leptin (R&D system, MOB00B), serum resistin (R&D system, MRSN00), serum FFA (Cayman Chemical, 700310).…”

“…IHC staining was performed as previously described 17 . Paraffin sections of 4 µm in size were deparaffinized and rehydrated.…”

“…Real-time PCR was performed as previously described 17 . Briefly, total RNA was extracted from ground tissue powder using TRIzol reagent (Invitrogen) according to the manufacturer’s instructions.…”