Hypothalamic AMPK-ER Stress-JNK1 Axis Mediates the Central Actions of Thyroid Hormones on Energy Balance

Thyroid hormones (THs) act in the brain to modulate energy balance. We show that central triiodothyronine (T3) regulates de novo lipogenesis in liver and lipid oxidation in brown adipose tissue (BAT) through the parasympathetic (PSNS) and sympathetic nervous system (SNS), respectively. Central T3 promotes hepatic lipogenesis with parallel stimulation of the thermogenic program in BAT. The action of T3 depends on AMP-activated protein kinase (AMPK)-induced regulation of two signaling pathways in the ventromedial nucleus of the hypothalamus (VMH): decreased ceramide-induced endoplasmic reticulum(ER) stress, which promotes BAT thermogenesis, and increased c-Jun N-terminal kinase (JNK) activation, which controls hepatic lipid metabolism. Of note, ablation of AMPK alpha 1 in steroidogenic factor 1 (SF1) neurons of the VMH fully recapitulated the effect of central T3, pointing to this population in mediating the effect of central THs on metabolism. Overall, these findings uncover the underlying pathways through which central T3 modulates peripheral metabolism.Peer reviewe

Pharmacological stimulation of p53 with low-dose doxorubicin ameliorates diet-induced nonalcoholic steatosis and steatohepatitis

Objective: Recent reports have implicated the p53 tumor suppressor in the regulation of lipid metabolism. We hypothesized that the pharmacological activation of p53 with low-dose doxorubicin, which is widely used to treat several types of cancer, may have beneficial effects on nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Methods: We used long-term pharmacological activation of p53 by i.p. or oral administration of low-dose doxorubicin in different animal models of NAFLD (high fat diet containing 45\% and 60\% kcal fat) and NASH (methionine- and choline-deficient diet and choline deficiency combined with high fat diet). We also administered doxorubicin in mice lacking p53 in the liver and in two human hepatic cells lines (HepG2 and THLE2). Results: The attenuation of liver damage was accompanied by the stimulation of fatty acid oxidation and decrease of lipogenesis, inflammation, and ER stress. The effects of doxorubicin were abrogated in mice with liver-specific ablation of p53. Finally, the effects of doxorubicin on lipid metabolism found in animal models were also present in two human hepatic cells lines, in which the drug stimulated fatty acid oxidation and inhibited de novo lipogenesis at doses that did not cause changes in apoptosis or cell viability. Conclusion: These data provide new evidence for targeting p53 as a strategy to treat liver disease. (C) 2017 The Authors. Published by Elsevier GmbH.This work has been supported by grants from Ministerio de Economia y Competitividad (CD: BFU2014-55871; RN: BFU2015-70664-R; GS: SAF2016-79126-R; ML: SAF2015-71026-R; PA: SAF2015-64352-R), Xunta de Galicia (ML: 2015-CP079; RN: 2015-CP080 and PIE13/00024), Heise Vest RHF (JF: Western Norway Regional Health Authority), Comunidad de Madrid (GS: S2010/BMD-2326); Govierno Vasco (PA: 2016-IT-336-10) and Fundacion AstraZeneca (R.N.) Centro de Investigacion Biomedica en Red (CIBER) de Fisiopatologia de la Obesidad y Nutricion (CIBERobn). CIBERobn is an initiative of the Institute de Salud Carlos III (ISCIII) of Spain which is supported by FEDER funds. The research leading to these results has also received funding from the European Community's Seventh Framework Programme under the following grant: RN: ERC StG-281408 and GS: ERC StG-260464.S

Hepatic p63 regulates steatosis via IKK beta/ER stress

p53 family members control several metabolic and cellular functions. The p53 ortholog p63 modulates cellular adaptations to stress and has a major role in cell maintenance and proliferation. Here we show that p63 regulates hepatic lipid metabolism. Mice with liver-specific p53 deletion develop steatosis and show increased levels of p63. Down-regulation of p63 attenuates liver steatosis in p53 knockout mice and in diet-induced obese mice, whereas the activation of p63 induces lipid accumulation. Hepatic overexpression of N-terminal transactivation domain TAp63 induces liver steatosis through IKK beta activation and the induction of ER stress, the inhibition of which rescues the liver functions. Expression of TAp63, IKK beta and XBP1s is also increased in livers of obese patients with NAFLD. In cultured human hepatocytes, TAp63 inhibition protects against oleic acid-induced lipid accumulation, whereas TAp63 overexpression promotes lipid storage, an effect reversible by IKK beta silencing. Our findings indicate an unexpected role of the p63/IKK beta/ER stress pathway in lipid metabolism and liver disease.We deeply thank Dr Manuel Serrano (Spanish National Cancer Research Center, CNIO, Spain) for kindly providing p53 null mice and critically reading the article. This work has been supported by grants from Ministerio de Economia y Competitividad (C.D.: BFU2014-55,871; R.N.: BFU2015-70,664-R; M.M.M.: BFU2013-44229-R; A.C.: SAF2016-79381-R, FEDER/UE; GS: SAF2013-43506-R; M.L.M.-C.: SAF2014-54658-R; M.L.: SAF2015-71026-R; P.A.: SAF2015-64352-R; B.G.-T.: FPI Severo Ochoa CNIC program SVP-2013-067639), Xunta de Galicia (M.L.: 2015-CP079; R.N.: 2015-CP080 and PIE13/00024), Comunidad de Madrid (G.S.: S2010/BMD-2326); Fondo de Investigaciones Sanitarias (M.M.: PI10/01692), Fundacion SEEN (R.N.), GV-Departamento de Salud-2013111114 (to M.L.M.-C.), ISCIII: PIE14/00031 (to M.L.M.-C.), Junta Provincial de Bizkaia-AECC (to M.L.M.-C.), AECC (T.C.D.); Basque Department of Industry, Tourism and Trade (Etortek) (A.C.), the BBVA foundation (A.C.), Fundacion AstraZeneca (R.N.) Centro de Investigacion Biomedica en Red (CIBER) de Fisiopatologia de la Obesidad y Nutricion (CIBERobn). CIBERobn is an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain, which is supported by FEDER funds. The participation of A.C. and A.Z.-L. as part of CIBERONC was co-funded with FEDER funds. The research leading to these results has also received funding from the European Community's Seventh Framework Programme under the following grant: A.C.: ERC StG-336343; R.N.: ERC StG-281408 and G.S.: ERC StG-260464.S