Myeloid p38 activation maintains macrophage-liver crosstalk and BAT thermogenesis through IL-12-FGF21 axis.

Obesity features excessive fat accumulation in several body tissues and induces a state of chronic low-grade inflammation that contributes to the development of diabetes, steatosis, and insulin resistance. Recent research has shown that this chronic inflammation is crucially dependent on p38 pathway activity in macrophages, suggesting p38 inhibition as a possible treatment for obesity comorbidities. Nevertheless, we report here that lack of p38 activation in myeloid cells worsens high-fat diet-induced obesity, diabetes, and steatosis. Deficient p38 activation increases macrophage IL-12 production, leading to inhibition of hepatic FGF21 and reduction of thermogenesis in the brown fat. The implication of FGF21 in the phenotype was confirmed by its specific deletion in hepatocytes. We also found that IL-12 correlates with liver damage in human biopsies, indicating the translational potential of our results. Our findings suggest that myeloid p38 has a dual role in inflammation and that drugs targeting IL-12 might improve the homeostatic regulation of energy balance in response to metabolic stress.S

Adiponectin accounts for gender differences in hepatocellular carcinoma incidence

Hepatocellular carcinoma (HCC) is the sixth most common cancer type and the fourth leading cause of cancer-related death. This cancer appears with higher incidence in men and during obesity; however, the specific mechanisms underlying this correlation are unknown. Adipose tissue, a key organ in metabolic syndrome, shows evident gender disparities in the production of adipokines. Levels of the important adipokine adiponectin decrease in men during puberty, as well as in the obese state. Here, we show that this decrease in adiponectin levels is responsible for the increased liver cancer risk in males. We found that testosterone activates the protein JNK in mouse and human adipocytes. JNK-mediated inhibition of adiponectin secretion increases liver cancer cell proliferation, since adiponectin protects against liver cancer development through the activation of AMP-activated protein kinase (AMPK) and p38α. This study provides insight into adipose tissue to liver crosstalk and its gender relation during cancer development, having the potential to guide strategies for new cancer therapeutics.G. Sabio is an investigator on the Ramón y Cajal Program. E. Manieri is a La Caixa Foundation fellow. L. Herrera-Melle is a fellow of the Ministerio de Educación, Cultura y Deporte (FPU15-05802). This study was funded by the following grants: G. Sabio was funded by the European Research Council (ERC 260464), European Foundation for the Study of Diabetes–Lilly, Ministerio de Ciencia, Innovación y Universidades (MICINN/SAF2016-79126-R), Comunidad de Madrid (B2017/BMD-3733), and BBVA Becas Leonardo a Investigadores y Creadores Culturales (Investigadores-BBVA-2017; IN[17]_BBM_BAS_0066); M. Marcos was funded by Instituto de Salud Carlos III and Federación Española de Enfermedades Raras (PI16/01548); and J.L. Torres was funded by Junta de Castilla y León GRS (1587/A/17). F.J. Cubero is a Ramón y Cajal Researcher (RYC-2014-15242) and a Gilead Liver Research Scholar 2018, and his work is supported by the Ministerio de Economia y Competitividad Retos (SAF2016-78711), Comunidad de Madrid (S2017/BMD-3727), The Alan Morement Memorial Fund Cholangiocarcinoma Charity (2018/117), the European Cooperation in Science and Technology Action (CA17112), and the European Foundation for Alcohol Research (EA14/18). L. Moran is a Comunidad de Madrid fellow (S2017/BMD-3727). The CNIC is supported by the Ministerio de Ciencia, Innovación y Universidades and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505).S

PPAR-γ Gene Expression in Human Adipose Tissue Is Associated with Weight Loss After Sleeve Gastrectomy

[EN] Background The peroxisome proliferator-activated receptor (PPAR)-γ plays a key role in adipose tissue differentiation and fat metabolism. However, it is unclear which factors may regulate its expression and whether obese patients have changes in adipose tissue expression of PPAR-γor potential regulators such as miR-27. Thus, our aims were to analyze PPAR-γ and miR-27 expression in adipose tissue of obese patients, and to correlate their levels with clinical variables. Subjects and Methods. We included 43 morbidly obese subjects who underwent sleeve gastrectomy (31 of them completed 1-year follow-up) and 19 non-obese subjects. mRNA expression of PPAR-γ1 and PPAR-γ2, miR-27a, and miR-27b was measured by qPCR in visceral and subcutaneous adipose tissue. Clinical variables and serum adipokine and hormone levels were correlated with PPAR-γ and miR-27 expression. In addition, a systematic review of the literature regarding PPAR-γ expression in adipose tissue of obese patients was performed. Results We found no differences in the expression of PPAR-γ and miR-27 in adipose tissue of obese patients vs. controls. The literature review revealed discrepant results regarding PPAR-γ expression in adipose tissue of obese patients. Of note, we described a significant negative correlation between pre-operative PPAR-γ1 expression in adipose tissue of obese patients and post-operative weight loss, potentially linked with insulin resistance markers. Conclusion PPAR-γ1 expression in adipose tissue is associated with weight loss after sleeve gastrectomy and may be used as a biomarker for response to surgery.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work was funded by the following grants to M.M.: ISCIII and FEDER, PI10/01692, PI16/01548, RD16/0017/0023, and I3SNS-INT12/049, L.H.C.: Junta de Castilla y León GRS 681/A/11, J.-L. T.: GRS 1587/A/17 and GRS1356/A/16, G.S.: ERC 260464, EFSD 2030, MICINNSAF2013-43506-R, and Comunidad de Madrid S2010/BMD-2326. G.S. is an investigator of the Ramón y Cajal Program.Publicación en abierto financiada por el Consorcio de Bibliotecas Universitarias de Castilla y León (BUCLE), con cargo al Programa Operativo 2014ES16RFOP009 FEDER 2014-2020 DE CASTILLA Y LEÓN, Actuación:20007-CL - Apoyo Consorcio BUCL

PPAR-γ Gene Expression in Human Adipose Tissue Is Associated with Weight Loss After Sleeve Gastrectomy

Background: The peroxisome proliferator-activated receptor (PPAR)-γ plays a key role in adipose tissue differentiation and fat metabolism. However, it is unclear which factors may regulate its expression and whether obese patients have changes in adipose tissue expression of PPAR-γor potential regulators such as miR-27. Thus, our aims were to analyze PPAR-γ and miR-27 expression in adipose tissue of obese patients, and to correlate their levels with clinical variables. Subjects and methods: We included 43 morbidly obese subjects who underwent sleeve gastrectomy (31 of them completed 1-year follow-up) and 19 non-obese subjects. mRNA expression of PPAR-γ1 and PPAR-γ2, miR-27a, and miR-27b was measured by qPCR in visceral and subcutaneous adipose tissue. Clinical variables and serum adipokine and hormone levels were correlated with PPAR-γ and miR-27 expression. In addition, a systematic review of the literature regarding PPAR-γ expression in adipose tissue of obese patients was performed. Results: We found no differences in the expression of PPAR-γ and miR-27 in adipose tissue of obese patients vs. controls. The literature review revealed discrepant results regarding PPAR-γ expression in adipose tissue of obese patients. Of note, we described a significant negative correlation between pre-operative PPAR-γ1 expression in adipose tissue of obese patients and post-operative weight loss, potentially linked with insulin resistance markers. Conclusion: PPAR-γ1 expression in adipose tissue is associated with weight loss after sleeve gastrectomy and may be used as a biomarker for response to surgeryThis work was funded by the following grants to M.M.: ISCIII and FEDER, PI10/01692, PI16/01548, RD16/0017/0023, and I3SNS-INT12/049, L.H.C.: Junta de Castilla y León GRS 681/A/11, J.-L. T.: GRS 1587/A/17 and GRS1356/A/16, G.S.: ERC 260464, EFSD 2030, MICINNSAF2013-43506-R, and Comunidad de Madrid S2010/BMD-2326. G.S. is an investigator of the Ramón y Cajal Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ISCIII,PI10/01692,Miguel Marcos,PI16/01548,Miguel Marcos,Gerencia regional de salud,junta de castilla y león,GRS 681/A/11,Lourdes Hernández-Cosido,J.-L. T,Lourdes Hernández-Cosido,Gerencia Regional de Salud,Junta de Castilla y León,GRS 1587/A/17,Jorge-Luis Torres,GRS1356/A/16,Jorge-Luis Torre

MKK6 controls T3-mediated browning of white adipose tissue

El aumento de la capacidad termogénica del tejido adiposo para mejorar el gasto de energía del organismo se considera una estrategia terapéutica prometedora para combatir la obesidad. Aquí nosotros informe que la expresión del activador MAPK p38 MKK6 está elevada en el tejido adiposo blanco de individuos obesos. Usando animales knockout y shRNA, mostramos que la eliminación de Mkk6 aumenta el gasto de energía y la capacidad termogénica del tejido adiposo blanco, protegiendo a los ratones contra la obesidad inducida por la dieta y el desarrollo de la diabetes. La eliminación de Mkk6 aumenta la expresión de UCP1 estimulada por T3 en los adipocitos, lo que aumenta su capacidad termogénica. De manera mecánica, demostramos que, en el tejido adiposo blanco, p38 se activa mediante una ruta alternativa que involucra AMPK, TAK y TAB. Nuestros resultados identifican MKK6 en los adipocitos como un posible objetivo terapéutico para reducir la obesidad.Increasing the thermogenic capacity of adipose tissue to enhance organismal energy expenditure is considered a promising therapeutic strategy to combat obesity. Here, we report that expression of the p38 MAPK activator MKK6 is elevated in white adipose tissue of obese individuals. Using knockout animals and shRNA, we show that Mkk6 deletion increases energy expenditure and thermogenic capacity of white adipose tissue, protecting mice against diet-induced obesity and the development of diabetes. Deletion of Mkk6 increases T3-stimulated UCP1 expression in adipocytes, thereby increasing their thermogenic capacity. Mechanistically, we demonstrate that, in white adipose tissue, p38 is activated by an alternative pathway involving AMPK, TAK, and TAB. Our results identify MKK6 in adipocytes as a potential therapeutic target to reduce obesity.• Guadalupe Sabio Buzo y Rebeca Acin Pérez pertenecen a Programa Ramón y Cajal • Elisa Manieri pertenece a Caixa • Ministerio de Economía y Competitividad. Proyecto FPI BES-2014-069332, para Valle Montalvo Romeral • Ministerio de Economía y Competitividad. Proyecto FPI BES-2011-043428, para Edgar Bernardo • Ministerio de Economía y Competitividad y FEDER SAF2016-79126-R y Comunidad de Madrid S2010 / BMD-2326, para Guadalupe Sabio Buzo • ISCIII y FEDER, PI10 / 01692 e I3SNS-INT12 / 049, para Miguel Marcos Martín • Junta de Castilla y León GRS 681 / A / 11, para Lourdes Hernández Cosido • Ministerio de Economía y Competitividad. BFU2015-70664-R, Xunta de Galicia 2015-CP080 y PIE13 / 00024, y ERC281408, para Rubén Nogueiras Pozo • Unión Europea. Becas europeas UE0 / MCA1108 y UE0 / MCA1201; y la Comunidad de Madrid CAM / API1009, para Rubén Nogueiras Pozo • Junta de Extremadura y FEDER BR15164, para Francisco Centeno Velázquez • Ministerio de Economía y Competitividad. . BFU2013-46109-R, para Clara V. Álvarez Villamarín • European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. ERC 260464peerReviewe

p38γ is essential for cell cycle progression and liver tumorigenesis

The cell cycle is a tightly regulated process that is controlled by the conserved cyclin-dependent kinase (CDK)–cyclin protein complex1. However, control of the G0-to-G1 transition is not completely understood. Here we demonstrate that p38 MAPK gamma (p38γ) acts as a CDK-like kinase and thus cooperates with CDKs, regulating entry into the cell cycle. p38γ shares high sequence homology, inhibition sensitivity and substrate specificity with CDK family members. In mouse hepatocytes, p38γ induces proliferation after partial hepatectomy by promoting the phosphorylation of retinoblastoma tumour suppressor protein at known CDK target residues. Lack of p38γ or treatment with the p38γ inhibitor pirfenidone protects against the chemically induced formation of liver tumours. Furthermore, biopsies of human hepatocellular carcinoma show high expression of p38γ, suggesting that p38γ could be a therapeutic target in the treatment of this disease

Adiponectin accounts for gender differences in hepatocellular carcinoma incidence

© 2019 Manieri et al.Hepatocellular carcinoma (HCC) is the sixth most common cancer type and the fourth leading cause of cancer-related death. This cancer appears with higher incidence in men and during obesity; however, the specific mechanisms underlying this correlation are unknown. Adipose tissue, a key organ in metabolic syndrome, shows evident gender disparities in the production of adipokines. Levels of the important adipokine adiponectin decrease in men during puberty, as well as in the obese state. Here, we show that this decrease in adiponectin levels is responsible for the increased liver cancer risk in males. We found that testosterone activates the protein JNK in mouse and human adipocytes. JNK-mediated inhibition of adiponectin secretion increases liver cancer cell proliferation, since adiponectin protects against liver cancer development through the activation of AMP-activated protein kinase (AMPK) and p38α. This study provides insight into adipose tissue to liver crosstalk and its gender relation during cancer development, having the potential to guide strategies for new cancer therapeutics.This study was funded by the following grants: G. Sabio was funded by the European Research Council (ERC 260464), European Foundation for the Study of Diabetes–Lilly, Ministerio de Ciencia, Innovación y Universidades (MICINN/SAF2016-79126-R), Comunidad de Madrid (B2017/BMD-3733), and BBVA Becas Leonardo a Investigadores y Creadores Culturales (Investigadores-BBVA-2017; IN[17]_BBM_BAS_0066); M. Marcos was funded by Instituto de Salud Carlos III and Federación Española de Enfermedades Raras (PI16/01548); and J.L. Torres was funded by Junta de Castilla y León GRS (1587/A/17). F.J. Cubero is a Ramón y Cajal Researcher (RYC-2014-15242) and a Gilead Liver Research Scholar 2018, and his work is supported by the Ministerio de Economia y Competitividad Retos (SAF2016-78711), Comunidad de Madrid (S2017/BMD-3727), The Alan Morement Memorial Fund Cholangiocarcinoma Charity (2018/117), the European Cooperation in Science and Technology Action (CA17112), and the European Foundation for Alcohol Research (EA14/18). L. Moran is a Comunidad de Madrid fellow (S2017/ ´ BMD-3727). The CNIC is supported by the Ministerio de Ciencia, Innovación y Universidades and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505)

p38α blocks brown adipose tissue thermogenesis through p38δ inhibition

<div><p>Adipose tissue has emerged as an important regulator of whole-body metabolism, and its capacity to dissipate energy in the form of heat has acquired a special relevance in recent years as potential treatment for obesity. In this context, the p38MAPK pathway has arisen as a key player in the thermogenic program because it is required for the activation of brown adipose tissue (BAT) thermogenesis and participates also in the transformation of white adipose tissue (WAT) into BAT-like depot called beige/brite tissue. Here, using mice that are deficient in p38α specifically in adipose tissue (p38α^Fab-KO), we unexpectedly found that lack of p38α protected against high-fat diet (HFD)-induced obesity. We also showed that p38α^Fab-KO mice presented higher energy expenditure due to increased BAT thermogenesis. Mechanistically, we found that lack of p38α resulted in the activation of the related protein kinase family member p38δ. Our results showed that p38δ is activated in BAT by cold exposure, and lack of this kinase specifically in adipose tissue (p38δ ^Fab-KO) resulted in overweight together with reduced energy expenditure and lower body and skin surface temperature in the BAT region. These observations indicate that p38α probably blocks BAT thermogenesis through p38δ inhibition. Consistent with the results obtained in animals, p38α was reduced in visceral and subcutaneous adipose tissue of subjects with obesity and was inversely correlated with body mass index (BMI). Altogether, we have elucidated a mechanism implicated in physiological BAT activation that has potential clinical implications for the treatment of obesity and related diseases such as diabetes.</p></div

p38α^Fab-KO mice are protected against diet-induced obesity and diabetes.

<p>(A) Body weight time course in Fab-Cre and p38α^Fab-KO male (8–10-wk-old) mice fed an HFD over 8 weeks. Data are presented as the increase above initial weight (left panel) or as total weight comparing mice fed an HDF with mice fed an ND (right panel). HFD-induced weight gain was significantly higher in Fab-Cre than p38α^Fab-KO mice (mean ± SEM; Fab-Cre HFD <i>n =</i> 10 mice; p38α^Fab-KO HFD <i>n =</i> 11 mice; Fab-Cre ND <i>n =</i> 9 mice; p38α^Fab-KO ND <i>n =</i> 8 mice). (B) NMR analysis of fat mass in p38α^Fab-KO and Fab-Cre mice after 8 weeks of HFD (mean ± SEM; Fab-Cre <i>n =</i> 10 mice; p38α^Fab-KO <i>n =</i> 8 mice). (C) Representative haematoxylin–eosin and oil red O staining of liver sections (Fab-Cre <i>n =</i> 6 mice; p38α^Fab-KO <i>n =</i> 6 mice; and 3 pictures from each mouse). Scale bar: 50 μm. (D) Fasting and fed blood glucose in Fab-Cre and p38α^Fab-KO mice fed the HFD (8 weeks) (mean ± SEM; Fab-Cre <i>n =</i> 10 mice; p38α^Fab-KO <i>n =</i> 11 mice). (E) GTT and ITT in Fab-Cre and p38α^Fab-KO mice fed the HFD for 8 weeks. Mice were fasted overnight (for GTT) or 1 hour (for ITT), and blood glucose concentration was measured in mice given intraperitoneal injections of glucose (1 g/kg of total body weight) or insulin (0.75 U/kg of total body weight) (mean ± SEM; Fab-Cre <i>n =</i> 10 mice; p38α^Fab-KO <i>n =</i> 11 mice). (F) Immunohistochemistry of eWAT sections using anti-GLUT4 (green), anti-Cav-1 (red) antibodies, and the nuclear dye DAPI (blue). Location of GLUT4 was analysed in mice treated without or with insulin (1.5 IU/kg) for 15 minutes after overnight fasting. Scale bar: 20 μm. (G) Representative haematoxylin–eosin BAT and eWAT sections (Fab-Cre <i>n =</i> 6 mice; p38α^Fab-KO <i>n =</i> 6 mice; and 3 pictures from each mouse). Scale bar: 50 μm. *<i>p</i> < 0.05, ***<i>p</i> < 0.001 Fab-Cre versus p38α^Fab-KO. ‘&&’ indicates <i>p</i> < 0.01, ‘&&&’ indicates <i>p</i> < 0.001 Fab-Cre ND versus Fab-Cre HFD (2-way ANOVA coupled with Bonferroni’s post-tests or <i>t</i> test or Welch’s test when variances were different). See also <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2004455#pbio.2004455.s015" target="_blank">S1 Data</a>. BAT, brown adipose tissue; Cav-1, caveolin-1; eWAT, epididymal fat; GLUT4, glucose transporter type 4; GTT, glucose tolerance test; HFD, high-fat diet; ITT, insulin tolerance test; ND, normal-chow diet; WAT, white adipose tissue.</p

p38α in human visceral fat inversely correlated with BMI and directly correlated with UCP1 in human visceral fat and sWAT.

<p>(A) mRNA levels of <i>Mapk14</i> (p38α) in visceral fat from lean individuals and individuals with obesity—mRNA expression was normalised to the amount of <i>Gapdh</i> mRNA. (B) Correlation between mRNA levels of <i>Mapk14</i> (p38α) and BMI (r² = −0,365; <i>p</i> = 0.001) or (C) <i>Ucp1</i> in visceral fat (r² = 0.316; <i>p</i> = 0.007). The mRNA levels of <i>Mapk14</i> (p38α) and <i>Ucp1</i> were determined by qRT-PCR (<i>n</i> = 71). (D) mRNA levels of <i>Mapk14</i> (p38α) in sWAT from lean individuals and individuals with obesity. mRNA expression was normalised to the amount of <i>Gapdh</i> mRNA. (E) Correlation between mRNA levels of <i>Mapk14</i> (p38α) and <i>Ucp1</i> in sWAT (r² = 0.320; <i>p</i> < 0.0001). Graph correlating mRNA <i>Mapk14</i> and log mRNA <i>Ucp1</i> is also shown. The mRNA levels of <i>Mapk14</i> (p38α) and <i>Ucp1</i> were determined by qRT-PCR (<i>n</i> = 168). See also <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2004455#pbio.2004455.s015" target="_blank">S1 Data</a>. Linear relationships between variables were tested using Pearson’s correlation coefficient. BMI, body mass index; qRT-PCR, quantitative real-time polymerase chain reaction; UCP1, uncoupling protein 1.</p