Nuevos mecanismos de regulación del balance energético. Papel de AMPK y del estrés del retículo endoplasmático hipotalámico

AMPK es un sensor celular que se activa en estado de baja energía. Las evidencias actuales vinculan la AMPK hipotalámica con la regulación central del balance energético. Sin embargo, cual es la isoforma de AMPK y el tipo neuronal que está mediando estos efectos todavía no se ha dilucidado. En esta Tesis, demostramos que la inhibición de AMPKα1 en las neuronas SF1 del núcleo ventromedial del hipotálamo protege contra la obesidad inducida por dieta al disminuir el estrés del retículo endoplasmático y la inflamación en el hipotálamo y al aumentar la termogénesis del tejido adiposo pardo y, posteriormente, el gasto de energía

Incendiary Leptin

Leptin is a hormone released by adipose tissue that plays a key role in the control of energy homeostasis through its binding to leptin receptors (LepR), mainly expressed in the hypothalamus. Most scientific evidence points to leptin’s satiating effect being due to its dual capacity to promote the expression of anorexigenic neuropeptides and to reduce orexigenic expression in the hypothalamus. However, it has also been demonstrated that leptin can stimulate (i) thermogenesis in brown adipose tissue (BAT) and (ii) the browning of white adipose tissue (WAT). Since the demonstration of the importance of BAT in humans 10 years ago, its study has aroused great interest, mainly in the improvement of obesity-associated metabolic disorders through the induction of thermogenesis. Consequently, several strategies targeting BAT activation (mainly in rodent models) have demonstrated great potential to improve hyperlipidemias, hepatic steatosis, insulin resistance and weight gain, leading to an overall healthier metabolic profile. Here, we review the potential therapeutic ability of leptin to correct obesity and other metabolic disorders, not only through its satiating effect, but by also utilizing its thermogenic properties

Lack of Hypophagia in CB1 Null Mice is Associated to Decreased Hypothalamic POMC and CART Expression

Background: Cumulative data indicate that the endocannabinoid system plays a major role in feeding behavior and energy balance. Genetic silencing of cannabinoid receptor type 1 (CB1) reduces body weight gain, independently of food intake. Methods: In this work, we investigated whether the hypothalamic neuropeptide expression pattern supports the absence of the anorexigenic response observed under constitutive CB1 ablation, by using neuronal CB1 conditional null mice (CamK-CB1-KO) and whole body CB1 null mice (CB1-KO). Results: Our data showed that both CB1 null models display a marked decrease in proopiomelanocortin (POMC) and cocaine-amphetamine-regulated transcript (CART) expression in the arcuate nucleus of the hypothalamus (ARC). Conclusions: This evidence suggests that a lack of hypophagia is associated with the suppression of ARC anorexigenic neuropeptides and that behavioral changes in food intake (or lack thereof) after constitutive CB1 ablation are likely mediated by impaired melanocortin and CART signaling in the hypothalamus.The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement nº 281854 of the ObERStress European Research Council Project (Dr López) and 245009 of the Neurofast project (Drs Nogueiras, Diéguez, and López); Xunta de Galicia (Dr Nogueiras: EM 2012/039 and 2012-CP069; Dr López: 2012-CP070); the Frank Mohn Foundation, Bergen (Dr Fernø); Instituto de Salud Carlos III (ISCIII; Dr López: PI12/01814 and PIE13/00024); and MINECO, co-funded by the FEDER Program of EU (Dr Nogueiras: RyC-2008-02219 and BFU2012-35255; Dr Diéguez: BFU2011-29102). CIBER de Fisiopatología de la Obesidad y Nutrición is an initiative of ISCIIIS

Hypothalamic Regulation of Liver and Muscle Nutrient Partitioning by Brain-Specific Carnitine Palmitoyltransferase 1C in Male Mice

Carnitine palmitoyltransferase (CPT) 1C, a brain-specific protein localized in the endoplasmic reticulum of neurons, is expressed in almost all brain regions. Based on global knockout (KO) models, CPT1C has demonstrated relevance in hippocampus-dependent spatial learning and in hypothalamic regulation of energy balance. Specifically, it has been shown that CPT1C is protective against high-fat diet-induced obesity (DIO), and that CPT1C KO mice show reduced peripheral fatty acid oxidation (FAO) during both fasting and DIO. However, the mechanisms mediating CPT1C-dependent regulation of energy homeostasis remain unclear. Here, we focus on the mechanistic understanding of hypothalamic CPT1C on the regulation of fuel selection in liver and muscle of male mice during energy deprivation situations, such as fasting. In CPT1C-deficient mice, modulation of the main hypothalamic energy sensors (50 adenosine monophosphate-activated protein kinase, Sirtuin 1, and mammalian target of rapamycin) was impaired and plasma catecholamine levels were decreased. Consequently, CPT1C-deficient mice presented defective fasting-induced FAO in liver, leading to higher triacylglycerol accumulation and lower glycogen levels. Moreover, muscle pyruvate dehydrogenase activity was increased, which was indicative of glycolysis enhancement. The respiratory quotient did not decrease in CPT1CKO mice after 48 hours of fasting, confirming a defective switch on fuel substrate selection under hypoglycemia. Phenotype reversion studies identified the mediobasal hypothalamus (MBH) as the main area mediating CPT1C effects on fuel selection. Overall, our data demonstrate that CPT1C in the MBH is necessary for proper hypothalamic sensing of a negative energy balance and fuel partitioning in liver and muscle

κ-Opioid Signaling in the Lateral Hypothalamic Area Modulates Nicotine-Induced Negative Energy Balance

Several studies have reported that nicotine, the main bioactive component of tobacco, exerts a marked negative energy balance. Apart from its anorectic action, nicotine also modulates energy expenditure, by regulating brown adipose tissue (BAT) thermogenesis and white adipose tissue (WAT) browning. These effects are mainly controlled at the central level by modulation of hypothalamic neuropeptide systems and energy sensors, such as AMP-activated protein kinase (AMPK). In this study, we aimed to investigate the kappa opioid receptor (κOR)/dynorphin signaling in the modulation of nicotine’s effects on energy balance. We found that body weight loss after nicotine treatment is associated with a down-regulation of the κOR endogenous ligand dynorphin precursor and with a marked reduction in κOR signaling and the p70 S6 kinase/ribosomal protein S6 (S6K/rpS6) pathway in the lateral hypothalamic area (LHA). The inhibition of these pathways by nicotine was completely blunted in κOR deficient mice, after central pharmacological blockade of κOR, and in rodents where κOR was genetically knocked down specifically in the LHA. Moreover, κOR-mediated nicotine effects on body weight do not depend on orexin. These data unravel a new central regulatory pathway modulating nicotine’s effects on energy balanceThis research was funded from the Xunta de Galicia (R.N.: 2016-PG057; ML: 2016-PG068); Ministerio de Economía y Competitividad (MINECO) co-funded by the FEDER Program of EU (R.N.: RTI2018-099413-B-I00; C.D.: BFU2017-87721-P; M.L.: RTI2018-101840-B-I00); Atresmedia Corporación (RN and ML); Fundación BBVA (RN); “la Caixa” Foundation (ID 100010434), under the agreements LCF/PR/HR19/52160016 (R.N.) and LCF/PR/HR19/52160022 (M.L.); European Foundation for the Study of Diabetes (R.N.), ERC Synergy Grant-2019-WATCH- 810331 (R.N.) and Western Norway Regional Health Authority (Helse Vest RHF) (J.F.). P.S.-C. is the recipient of a fellowship from Xunta de Galicia (ED481B 2018/050). The CiMUS is supported by the Xunta de Galicia (2016-2019, ED431G/05). CIBER de Fisiopatología de la Obesidad y Nutrición is an initiative of ISCIIIS

A Functional Link between AMPK and Orexin Mediates the Effect of BMP8B on Energy Balance

AMP-activated protein kinase (AMPK) in the ventromedial nucleus of the hypothalamus (VMH) and orexin (OX) in the lateral hypothalamic area (LHA) modulate brown adipose tissue (BAT) thermogenesis. However, whether these two molecular mechanisms act jointly or independently is unclear. Here, we show that the thermogenic effect of bone morphogenetic protein 8B (BMP8B) is mediated by the inhibition of AMPK in the VMH and the subsequent increase in OX signaling via the OX receptor 1 (OX1R). Accordingly, the thermogenic effect of BMP8B is totally absent in ox-null mice. BMP8B also induces browning of white adipose tissue (WAT), its thermogenic effect is sexually dimorphic (only observed in females), and its impact on OX expression and thermogenesis is abolished by the knockdown of glutamate vesicular transporter 2 (VGLUT2), implicating glutamatergic signaling. Overall, our data uncover a central network controlling energy homeostasis that may be of considerable relevance for obesity and metabolic disordersThe research leading to these results received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement 281854 the ObERStress project (M.L.), Junta de Andalucía (M.T.-S., P08-CVI-03788 and P12-FQM-01943), Xunta de Galicia (M.L., 2015-CP079; and R.N., 2015-CP080 and PIE13/00024), MINECO co-funded by FEDER (C.D., BFU2014-55871-P; R.N., BFU2015-70664-R; M.T.-S., BFU2014-57581-P; and M.L., SAF2015-71026-R and BFU2015-70454-REDT/Adipoplast). I.G.-G. is a recipient of a fellowship from Ministerio de Educación, Cultura y Deporte (FPU12/01827). CIBER de Fisiopatología de la Obesidad y Nutrición is an initiative of ISCIII. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscriptS

Central Ceramide-Induced Hypothalamic Lipotoxicity and ER Stress Regulate Energy Balance

Hypothalamic endoplasmic reticulum (ER) stress is a key mechanism leading to obesity. Here, we demonstrate that ceramides induce lipotoxicity and hypothalamic ER stress, leading to sympathetic inhibition, reduced brown adipose tissue (BAT) thermogenesis, and weight gain. Genetic overexpression of the chaperone GRP78/BiP (glucoseregulated protein 78 kDa/binding immunoglobulin protein) in the ventromedial nucleus of the hypothalamus (VMH) abolishes ceramide action by reducing hypothalamic ER stress and increasing BAT thermogenesis, which leads to weight loss and improved glucose homeostasis. The pathophysiological relevance of this mechanism is demonstrated in obese Zucker rats, which show increased hypothalamic ceramide levels and ER stress. Overexpression of GRP78 in the VMH of these animals reduced body weight by increasing BAT thermogenesis as well as decreasing leptin and insulin resistance and hepatic steatosis. Overall, these data identify a triangulated signaling network involving central ceramides, hypothalamic lipotoxicity/ER stress, and BAT thermogenesis as a pathophysiological mechanism of obesity

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

Initial age-associated metabolic alterations in white and brown fat depots: effect of long-term caloric restriction

Resumen del póster presentado al 6th Symposium on Biomedical Research: Advances and Perspectives in Molecular Endocrinology "In Homage to Gabriella Morreale", celebrado en el Instituto de Investigaciones Biomédicas Alberto Sols (IIBM-CSIC) el 31 de mayo de 2019.Changes in the body composition such as high adiposity and sarcopeny occur during aging. These changes are usually associated to metabolic alterations like insulin resistance, type 2 diabetes and metabolic syndrome. Adipose tissue is not homogeneous and dysfunction of white adipose tissue (WAT) and brown adipose tissue (BAT) can develop differently during aging. Our aim is to study different WAT and BAT depots at middle-age to detect the initial signals of alteration. Moreover, we have studied the effect of the long-term caloric restriction (CR) and its benefits. Sv129 mice 3 and 12-month-old mice fed ad libitum and 12-month-old mice fed with a 20% CR (3m, 12m and 12mCR, respectively) have been used. RT-PCR has been employed to study lipid metabolism gene expression in eWAT, scWAT and BAT. Moreover, circulating serum and BAT thyroid hormones levels were measured by radioimmunoassay (RIA). 12m animals showed insulin resistance and lower adiponectin levels in plasma compared with 3m. Expression of insulin pathway (Glut4, Irs1), lipogenesis (Fas, Scd1) and lipolysis (Hsl, Atgl, Pparα) genes was decreased in scWAT of 12m animals, but not in eWAT. Furthermore, UCP-1 expression was significantly lower in scWAT of aged mice compared with younger mice, suggesting a decrease in beige adipose tissue associated to aging. On the other hand, we found decreased expression of some BAT-selective genes12m animals such as Ucp1, βAr. CR recovered the expression levels to those of 3m mice. Thyroxine (T4) in plasma did not reach significance among middle-aged and young animals, however triiodothyronine (T3) levels were lower in 12m than 3m and 12mCR mice. Dio2 expression, T4 and T3 concentrations in BAT followed a similar pattern, a decrease in 12m mice and an increase in CR mice. Although eWAT has been described as the most dangerous tissue from the metabolic point of view, our data could suggest an earlier metabolic alteration in scWAT than in eWAT. Our findings prompt that CR could revert the initial agerelated alterations in scWAT. In agreement, we point to alteration of thyroid axis status with age is an important factor contributing to BAT dysfunction at middle-age, which can be ameliorated by CR.BFU2016-78951-R, B2017BMD-3684, BFU2017-90578-REDT, Fundacion Mapfre, CAMS210/BMD-2433.Peer reviewe