Twf1 regulates adipocyte proliferation and differentiation through Yap nucleus accumulation.
Twf1 knockdown significantly enhances adipocyte proliferation, while its overexpression reduces both proliferation and differentiation, indicating its potential role in obesity development.
Where it sits
this study against the rest of the adipotide (prohibitin-tp01) corpusSummary and findings
This study investigates the role of Twinfilin-1 (Twf1) in adipocyte proliferation and differentiation in the context of obesity. It was conducted in obese mice induced by a high-fat diet and assessed the effects of Twf1 knockdown and overexpression in C3H10T1/2 preadipocytes. Key findings indicate that Twf1 knockdown enhanced adipocyte proliferation and differentiation, while overexpression had the opposite effect.
Abstract
Obesity involves white adipose tissue (WAT) expansion via hyperplasia and hypertrophy. Impaired adipocyte proliferation leads to pathological hypertrophy, inflammation and metabolic dysfunction. Aberrant F‑actin turnover disrupts proliferation/differentiation. Twinfilin‑1 (Twf1) regulates actin dynamics and cell proliferation/differentiation, but its role in adipocytes is unknown. Obese mice were induced by high‑fat diet (HFD) and weight loss by calorie restriction. Inguinal, epididymal and scapular adipose tissues were collected. Proteomics used pressure cycling, DDA library building and DIA quantification. Twf1 expression was validated by RT‑qPCR and Western blot. In C3H10T1/2 preadipocytes, Twf1 knockdown and overexpression were established. Differentiation was induced with dexamethasone, rosiglitazone, insulin and IBMX. Adipogenesis and proliferation were assessed by RT‑qPCR, Western blot, Oil Red O and CCK8. Nuclear‑cytoplasmic fractionation evaluated Yap localization and HIPPO activity. HFD mice showed weight gain, dyslipidemia and adipocyte hypertrophy, reversed by weight loss. Proteomics identified 43 proteins intersecting obesity, weight loss, and actin‑related datasets; Twf1 was upregulated in obese epididymal/inguinal fat and downregulated after weight loss. In C3H10T1/2 cells, Twf1 knockdown enhanced white adipocyte differentiation (upregulated Pparg2, Fsp27, Fabp4) and proliferation (2.28‑fold vs. control), promoted Yap nuclear accumulation, and inhibited HIPPO signalling. Twf1 overexpression reduced differentiation, lipid droplets, and proliferation (to 44.7% of control). Twf1 is upregulated in white/beige adipose tissue of obese mice and downregulated after weight loss. Twf1 knockdown promotes Yap nuclear accumulation, inhibits HIPPO and enhances adipocyte proliferation and white adipocyte maturation, indicating a key role in obesity development.
Background
The paper addresses the mechanisms of adipocyte proliferation and differentiation, particularly in the context of obesity, where white adipose tissue expansion occurs through both hyperplasia and hypertrophy. Previous research has established that impaired adipocyte proliferation can lead to metabolic dysfunction and inflammation. Understanding the role of Twf1 in these processes is significant as it may provide insights into potential targets for obesity-related interventions.
Methods
The study utilized a high-fat diet to induce obesity in mice, followed by weight loss through calorie restriction. Adipose tissues were collected from various depots, and proteomics techniques were employed for analysis. In C3H10T1/2 preadipocytes, Twf1 knockdown and overexpression were performed, with differentiation induced using dexamethasone, rosiglitazone, insulin, and IBMX. Primary outcomes included adipogenesis and proliferation measured through RT-qPCR, Western blot, Oil Red O staining, and CCK8 assays.
Results
The primary finding indicates that Twf1 knockdown resulted in a 2.28-fold increase in adipocyte proliferation compared to control. Additionally, Twf1 overexpression led to a reduction in differentiation and proliferation to 44.7% of control levels. Twf1 was found to be upregulated in obese adipose tissues and downregulated following weight loss.
Interpretation
The findings suggest that Twf1 plays a critical role in regulating adipocyte behavior in obesity, aligning with previous literature that links adipocyte proliferation to metabolic health. However, the effect size of Twf1 overexpression reducing proliferation to 44.7% of control may not be clinically significant. The study's reliance on rodent models and in vitro conditions limits the generalizability of these results to human populations.
Key findings
- Twf1 knockdown enhanced white adipocyte differentiation (upregulated Pparg2, Fsp27, Fabp4).
- Twf1 knockdown increased proliferation by 2.28-fold vs. control.
- Twf1 overexpression reduced differentiation and proliferation to 44.7% of control.
Limitations
- rodent models may not fully translate to humans
- in vitro findings may not reflect in vivo conditions
- no long-term follow-up reported