Pulmonary Hypertension in Obese Mice Is Accompanied by a Reduction in PPAR-γ Expression in Pulmonary Artery

Gonçalves, Adilson R.; Rocha, George J. M.; Marin, Rodrigo Miguel; Camargo, Rafael Ludemann; Santos, Andrey dos; Carmo, Helison do; Guadagnini, Dioze; Petrucci, Orlando; Moyses, Zenaide P.; Salemi, Vera Maria Cury; Oliveira, Alexandre G.; Saad, Mário José Abdalla

doi:10.3389/fendo.2021.701994

Cited by 6 publications

(9 citation statements)

References 44 publications

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“…Eight-week-old male mice were maintained under specific pathogen-free conditions in a regimen of 12-h dark, 12-h light cycles, and room temperature of 21 °C. The animals were submitted to a HFD for 8 wk (HFD) ( 61 ) to induce obesity, insulin resistance, and glucose intolerance. Food and water were ad libitum.…”

Section: Methodsmentioning

confidence: 99%

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Metformin acts in the gut and induces gut-liver crosstalk

Tobar

Rocha

Santos

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Metformin is the most prescribed drug for DM2, but its site and mechanism of action are still not well established. Here, we investigated the effects of metformin on basolateral intestinal glucose uptake (BIGU), and its consequences on hepatic glucose production (HGP). In diabetic patients and mice, the primary site of metformin action was the gut, increasing BIGU, evaluated through PET-CT. In mice and CaCo2 cells, this increase in BIGU resulted from an increase in GLUT1 and GLUT2, secondary to ATF4 and AMPK. In hyperglycemia, metformin increased the lactate (reducing pH and bicarbonate in portal vein) and acetate production in the gut, modulating liver pyruvate carboxylase, MPC1/2, and FBP1, establishing a gut-liver crosstalk that reduces HGP. In normoglycemia, metformin-induced increases in BIGU is accompanied by hypoglycemia in the portal vein, generating a counter-regulatory mechanism that avoids reductions or even increases HGP. In summary, metformin increases BIGU and through gut-liver crosstalk influences HGP.

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Section: Methodsmentioning

confidence: 99%

“…Then, the liver, colon, and the final third of ileum were extracted, washed, minced coarsely, and homogenized immediately in the extraction buffer. Experiments utilizing immunoprecipitation or immunoblotting were performed according to previously published work ( 61 ).…”

Section: Metformin Administration Protocolmentioning

confidence: 99%

Metformin acts in the gut and induces gut-liver crosstalk

Tobar

Rocha

Santos

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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“…The correlations between obesity, IR, dyslipidemia and cardiovascular disease are well established. However, the link between these diseases and PAH development has only recently been explored ( 18 ).…”

Section: Correlation Of Ir With Pahmentioning

confidence: 99%

“…Data coming from different sources demonstrated a reduction in expression of the PPARg in PAH patients ( 18 , 38 , 39 ). PPARg is a nuclear receptor and transcription factor that regulates adipogenesis and glucose metabolism.…”

Section: A Common Ground: Molecular Determinants Of the Association B...mentioning

confidence: 99%

“…Treatment with the agonist of PPARg (Roziglitazone), an insulin sensitizer and antidiabetic drug, can reverse the PH ( 40 ) in those mice. In this regard, treatment with Pioglitazone (PIO), another agonist of PPARg, was also capable of improving IR and PH in mice treated with an HFD, with an increase in adiponectin levels ( 18 ).…”

Section: A Common Ground: Molecular Determinants Of the Association B...mentioning

confidence: 99%

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Pulmonary hypertension and insulin resistance: a mechanistic overview

Zanotto,

Gonçalves,

Saad

2024

Front. Endocrinol.

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Pulmonary arterial hypertension (PAH) is a vascular remodeling disease, characterized by increased blood pressure levels in pulmonary circulation, leading to a restriction in the circulation flow and heart failure. Although the emergence of new PAH therapies has increased survival rates, this disease still has a high mortality and patients that receive diagnosis die within a few years. The pathogenesis of PAH involves multiple pathways, with a complex interaction of local and distant cytokines, hormones, growth factors, and transcription factors, leading to an inflammation that changes the vascular anatomy in PAH patients. These abnormalities involve more than just the lungs, but also other organs, and between these affected organs there are different metabolic dysfunctions implied. Recently, several publications demonstrated in PAH patients a disturbance in glucose metabolism, demonstrated by higher levels of glucose, insulin, and lipids in those patients. It is possible that a common molecular mechanism can have a significant role in this connection. In this regard, this narrative review intends to focus on the recent papers that mainly discuss the molecular determinants between insulin resistance (IR) associated PAH, which included obesity subclinical inflammation induced IR, PPAR gamma and Adiponectin, BMPR2, mitochondrial dysfunction and endoplasmic reticulum stress. Therefore, the following review will summarize some of the existing data for IR associated PAH, focusing on the better understanding of PAH molecular mechanisms, for the development of new translational therapies.

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