Abstract
Obesity and related disorders have increasingly become global health problems over the years. In recent years, obesity has been recognized as the most important risk factor for a variety of diseases including cardiovascular diseases, type 2 diabetes, steatohepatitis, and cancer. The medical anti-obesity treatment is to intervene in the metabolic process of adipocytes by suppressing adipogenesis and promoting lipolysis. The Phosphodiesterase-4 (PDE4) pathway is involved in fat mass control and metabolic regulation. The present study aimed to investigate the effects of Roflumilast, a selective PDE4 inhibitor, on the differentiation of 3T3-L1 cells and the high fat diet-induced obesity in mice. We showed that treatment with Roflumilast inhibited lipid accumulation and triglycerides storage in mature 3T3-L1 cells, suggesting that Roflumilast suppressed adipogenesis. Mechanistically, we found that Roflumilast decreased the differentiation-induced expression of the adipogenesis genes including SREBP1C, FABP4, and Glut4, as well as their regulators including PPAR-γ and C/EBPα. Moreover, we proved that the effect of Roflumilast was dependent on the activation of the metabolic regulator AMPKα. The treatment with Roflumilast remarkably decreased the animals’ body weight, visceral adipose tissue weight, and adipocyte size in high fat diet-induced obese mice. In conclusion, our study revealed that Roflumilast suppressed adipogenesis and promoted lipolysis in cell culture and mice models via AMPK-mediated inhibition of PPAR-γ and C/EBPα. These findings imply roflumilast could have therapeutic potential in obesity-related diseases.
Highlights
The prevalence of obesity has become a significant health burden in many countries
We found that blockage of AMPKa by compound C almost abolished the amelioration of Roflumilast on Peroxisome proliferator-activated receptor (PPAR)-g and C/EBPa
The biological strategy to intervene with overweight and obesity is to suppress adipogenesis and increase the metabolism of adipocytes
Summary
The prevalence of obesity has become a significant health burden in many countries. Driven mainly by unhealthy dietary habits and sedentary lifestyles, obesity is a significant risk factor for major chronic diseases, including type 2 diabetes and cardiovascular diseases [1]. Adipose tissue is mainly made up of lipid-rich adipocytes, and it comprises about 20% of total body weight in healthy individuals. As the central metabolic organ, the main function of adipose tissue is to store energy and maintain homeostasis. Adipocytes store the energy as lipid droplets and secrete different adipokines to regulate energy homeostasis. In response to the oversupply of energy, adipocytes can rapidly expand their number and increase their size to store triglycerides (TG). The expansion of adipocytes is characterized by the differentiation of preadipocytes into mature adipocytes, a process called adipogenesis [2]
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