Dataset Information

Specific knockout of p85? in brown adipose tissue induces resistance to high-fat diet-induced obesity and its metabolic complications in male mice.

ABSTRACT:

Objective

An increase in mass and/or brown adipose tissue (BAT) functionality leads to an increase in energy expenditure, which may be beneficial for the prevention and treatment of obesity. Moreover, distinct class I PI3K isoforms can participate in metabolic control as well as in systemic dysfunctions associated with obesity. In this regard, we analyzed in vivo whether the lack of p85? in BAT (BATp85?KO) could modulate the activity and insulin signaling of this tissue, thereby improving diet-induced obesity and its associated metabolic complications.

Methods

We generated BATp85?KO mice using Cre-LoxP technology, specifically deleting p85? in a conditional manner. To characterize this new mouse model, we used mice of 6 and 12 months of age. In addition, BATp85?KO mice were submitted to a high-fat diet (HFD) to challenge BAT functionality.

Results

Our results suggest that the loss of p85? in BAT improves its thermogenic functionality, high-fat diet-induced adiposity and body weight, insulin resistance, and liver steatosis. The potential mechanisms involved in the improvement of obesity include (1) increased insulin signaling and lower activation of JNK in BAT, (2) enhanced insulin receptor isoform B (IRB) expression and association with IRS-1 in BAT, (3) lower production of proinflammatory cytokines by the adipose organ, (4) increased iWAT browning, and (5) improved liver steatosis.

Conclusions

Our results provide new mechanisms involved in the resistance to obesity development, supporting the hypothesis that the gain of BAT activity induced by the lack of p85? has a direct impact on the prevention of diet-induced obesity and its associated metabolic complications.

SUBMITTER: Gomez-Hernandez A

PROVIDER: S-EPMC6977168 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Specific knockout of p85α in brown adipose tissue induces resistance to high-fat diet-induced obesity and its metabolic complications in male mice.

Gomez-Hernandez Almudena A Lopez-Pastor Andrea R AR Rubio-Longas Carlota C Majewski Patrik P Beneit Nuria N Viana-Huete Vanesa V García-Gómez Gema G Fernandez Silvia S Hribal Marta Letizia ML Sesti Giorgio G Escribano Oscar O Benito Manuel M

Molecular metabolism 20191109

<h4>Objective</h4>An increase in mass and/or brown adipose tissue (BAT) functionality leads to an increase in energy expenditure, which may be beneficial for the prevention and treatment of obesity. Moreover, distinct class I PI3K isoforms can participate in metabolic control as well as in systemic dysfunctions associated with obesity. In this regard, we analyzed in vivo whether the lack of p85α in BAT (BATp85αKO) could modulate the activity and insulin signaling of this tissue, thereby improvin ...[more]

PMID: 31918912

Similar Datasets

Project description:Obesity is associated with chronic inflammation which plays a critical role in the development of cardiovascular dysfunction. Because the adaptor protein caspase recruitment domain-containing protein 9 (CARD9) in macrophages regulates innate immune responses via activation of pro-inflammatory cytokines, we hypothesize that CARD9 mediates the pro-inflammatory signaling associated with obesity en route to myocardial dysfunction. C57BL/6 wild-type (WT) and CARD9(-/-) mice were fed normal diet (ND, 12% fat) or a high fat diet (HFD, 45% fat) for 5months. At the end of 5-month HFD feeding, cardiac function was evaluated using echocardiography. Cardiomyocytes were isolated and contractile properties were measured. Immunofluorescence was performed to detect macrophage infiltration in the heart. Heart tissue homogenates, plasma, and supernatants from isolated macrophages were collected to measure the concentrations of pro-inflammatory cytokines using ELISA kits. Western immunoblotting analyses were performed on heart tissue homogenates and isolated macrophages to explore the underlying signaling mechanism(s). CARD9 knockout alleviated HFD-induced insulin resistance and glucose intolerance, prevented myocardial dysfunction with preserved cardiac fractional shortening and cardiomyocyte contractile properties. CARD9 knockout also significantly decreased the number of infiltrated macrophages in the heart with reduced myocardium-, plasma-, and macrophage-derived cytokines including IL-6, IL-1β and TNFα. Finally, CARD9 knockout abrogated the increase of p38 MAPK phosphorylation, the decrease of LC3BII/LC3BI ratio and the up-regulation of p62 expression in the heart induced by HFD feeding and restored cardiac autophagy signaling. In conclusion, CARD9 knockout ameliorates myocardial dysfunction associated with HFD-induced obesity, potentially through reduction of macrophage infiltration, suppression of p38 MAPK phosphorylation, and preservation of autophagy in the heart.