Roflumilast Suppresses Adipogenic Differentiation via AMPK Mediated Pathway

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.

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Trans-palmitoleic Acid Reduces Adiposity via Increased Lipolysis in a Rodent Model of Diet-Induced Obesity

British Journal Of Nutrition ◽

10.1017/s0007114521001501 ◽

2021 ◽

pp. 1-24

Author(s):

L. Irasema Chávaro-Ortiz ◽

Brenda D. Tapia-Vargas ◽

Mariel Rico-Hidalgo ◽

Ruth Gutiérrez-Aguilar ◽

María E. Frigolet

Keyword(s):

Adipose Tissue ◽

Lipid Metabolism ◽

Visceral Adipose Tissue ◽

High Fat Diet ◽

Palmitoleic Acid ◽

Rodent Model ◽

Adipocyte Size ◽

High Fat ◽

Diet Induced Obesity ◽

Visceral Adipose

Abstract Obesity is defined as increased adiposity, which leads to metabolic disease. The growth of adipose tissue depends on its capacity to expand, through hyperplasia or hypertrophy, in order to buffer energy surplus. Also, during the establishment of obesity, adipose tissue expansion reflects adipose lipid metabolism (lipogenesis and/or lipolysis). It is well known that dietary factors can modify lipid metabolism promoting or preventing the development of metabolic abnormalities that concur with obesity. Trans-palmitoleic acid (TP), a biomarker of dairy consumption, has been associated with reduced adiposity in clinical studies. Thus, we aimed to evaluate the effect of TP over adiposity and lipid metabolism-related genes in a rodent model of diet-induced obesity (DIO). To fulfil this aim, we fed C57BL/6 mice with a Control or a High Fat diet, added with or without TP (3g/kg diet), during 11 weeks. Body weight and food intake were monitored, fat pads were weighted, histology of visceral adipose tissue was analysed, and lipid metabolism-related gene expression was explored by qPCR. Results show that TP consumption prevented weight gain induced by high fat diet, reduced visceral adipose tissue weight, and adipocyte size, while increasing the expression of lipolytic molecules. In conclusion, we show for the first time that TP influences adipose tissue metabolism, specifically lipolysis, resulting in decreased adiposity and reduced adipocyte size in a DIO mice model.

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Treatment potential of LPCN 1144 on liver health and metabolic regulation in a non-genomic, high fat diet induced NASH rabbit model

Journal of Endocrinological Investigation ◽

10.1007/s40618-021-01522-7 ◽

2021 ◽

Author(s):

P. Comeglio ◽

E. Sarchielli ◽

S. Filippi ◽

I. Cellai ◽

G. Guarnieri ◽

...

Keyword(s):

Hepatic Fibrosis ◽

High Fat Diet ◽

Metabolic Regulation ◽

Therapeutic Potential ◽

Rabbit Model ◽

Free Testosterone ◽

Preclinical Model ◽

High Fat ◽

Liver Health ◽

Metabolic Dysfunctions

Abstract Purpose Low free testosterone (T) level in men is independently associated with presence and severity of Non-Alcoholic Steatohepatitis (NASH). The histological and molecular effects of oral testosterone prodrug LPCN 1144 treatment on hepatic fibrosis and NASH features are unknown. A metabolic syndrome-induced NASH model in rabbits consuming high fat diet (HFD) has been previously used to assess treatment effects of injectable T on hepatic fibrosis and NASH features. Here we present results on LPCN 1144 in this HFD-induced, NASH preclinical model. Methods Male rabbits were randomly assigned to five groups: regular diet (RD), HFD, HFD + 1144 vehicle (HFD + Veh), HFD + 1144 (1144), and HFD + 1144 + α-tocopherol (1144 + ALPHA). Rabbits were sacrificed after 12 weeks for liver histological, biochemical and genetic analyses. Histological scores were obtained through Giemsa (inflammation), Masson’s trichrome (steatosis and ballooning), and Picrosirius Red (fibrosis) staining. Results Compared to RD, HFD and HFD + Veh significantly worsened NASH features and hepatic fibrosis. Considering HFD and HFD + Veh arms, histological and biomarker features were not significantly different. Both 1144 and 1144 + ALPHA arms improved mean histological scores of NASH as compared to HFD arm. Importantly, percentage of fibrosis was improved in both 1144 (p < 0.05) and 1144 + ALPHA (p = 0.05) treatment arms vs. HFD. Both treatment arms also reduced HFD-induced inflammation and fibrosis mRNA markers. Furthermore, 1144 treatments significantly improved HFD-induced metabolic dysfunctions. Conclusions Histological and biomarker analyses demonstrate that LPCN 1144 improved HFD-induced hepatic fibrosis and NASH biochemical, biomolecular and histochemical features. These preclinical findings support a therapeutic potential of LPCN 1144 in the treatment of NASH and of hepatic fibrosis.

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