Decoding the Role of Gut-Microbiome in the Food Addiction Paradigm

Eating behaviour is characterised by a solid balance between homeostatic and hedonic regulatory mechanisms at the central level and highly influenced by peripheral signals. Among these signals, those generated by the gut microbiota have achieved relevance in recent years. Despite this complex regulation, under certain circumstances eating behaviour can be deregulated becoming addictive. Although there is still an ongoing debate about the food addiction concept, studies agree that patients with eating addictive behaviour present similar symptoms to those experienced by drug addicts, by affecting central areas involved in the control of motivated behaviour. In this context, this review tries to summarise the main data regarding the role of the gut microbiome in eating behaviour and how a gut dysbiosis can be responsible for a maladaptive behaviour such as “food addiction”Financial support from the Xunta de Galicia (Centro singular de investigación de Galicia accreditation 2019-2022- ED431G 2019/02) and the European Union (European Regional Development Fund-ERDF) is gratefully acknowledged. Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición (CIBERobn) is an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain, which is supported by ERDF funds. MGN is recipient of “Juan de la Cierva-Incorporación” fellowship (IJCI-2017-32606) from Ministerio de Ciencia, Innovación y Universidades, SpainS

Neonatal events, such as androgenization and postnatal overfeeding, modify the response to ghrelin

It is currently accepted that ambient, non-genetic factors influence perinatal development and evoke structural and functional changes that may persist throughout life. Overfeeding and androgenization after birth are two of these key factors that could result in "metabolic imprinting" of neuronal circuits early in life and, thereby, increase the body weight homeostatic "set point", stimulate appetite, and result in obesity. Our aim was to determine the influence of these obesogenic factors on the response to ghrelin. We observed the expected orexigenic effect of ghrelin regardless of the nutritional or hormonal manipulations to which the animals were subjected to at early postnatal development and this effect remained intact at later stages of development. In fact, ghrelin responses increased significantly when the animals were subjected to one of the two manipulations, but not when both were combined. An increased response to ghrelin could explain the obese phenotype displayed by individuals with modified perinatal environment.Ministerio de Educacion y CienciaInstituto de Salud Carlos IIIEuropean Community´s Seventh Framework Programm

Irisin, Two Years Later

In January 2012, Boström and colleagues identified a new muscle tissue secreted peptide, which they named irisin, to highlight its role as a messenger that comes from skeletal muscle to other parts of the body. Irisin is a cleaved and secreted fragment of FNDC5 (also known as FRCP2 and PeP), a member of fibronectin type III repeat containing gene family. Major interest in this protein arose because of its great therapeutic potential in diabetes and perhaps also therapy for obesity. Here we review the most important aspects of irisin's action and discuss its involvement in energy and metabolic homeostasis and whether the beneficial effects of exercise in these disease states could be mediated by this protein. In addition the effects of irisin at the central nervous system (CNS) are highlighted. It is concluded that although current and upcoming research on irisin is very promising it is still necessary to deepen in several aspects in order to clarify its full potential as a meaningful drug target in human disease states

Neonatal events, such as androgenization and postnatal overfeeding, modify the response to ghrelin

It is currently accepted that ambient, non-genetic factors influence perinatal development and evoke structural and functional changes that may persist throughout life. Overfeeding and androgenization after birth are two of these key factors that could result in “metabolic imprinting” of neuronal circuits early in life and, thereby, increase the body weight homeostatic “set point”, stimulate appetite and result in obesity. Our aim was to determine the influence of these obesogenic factors on the response to ghrelin. We observed the expected orexigenic effect of ghrelin regardless of the nutritional or hormonal manipulations to which the animals were subjected to at early postnatal development and this effect remained intact at later stages of development. In fact, ghrelin responses increased significantly when the animals were subjected to one of the two manipulations, but not when both were combined. An increased response to ghrelin could explain the obese phenotype displayed by individuals with modified perinatal environment.This work has been supported by grants from Ministerio de Educacion y Ciencia (CD: BFU2011-29102) and Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición (CIBERobn). CIBERobn is an initiative of the Instituto 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: CD: FP7/2007-2013: n° 245009: NeuroFASTS

Hypothalamic mTOR signaling mediates the orexigenic action of ghrelin

Current evidence suggests that ghrelin, a stomach derived peptide, exerts its orexigenic action through specific modulation of Sirtuin1 (SIRT1)/p53 and AMP-activated protein kinase (AMPK) pathways, which ultimately increase the expression of agouti-related protein (AgRP) and neuropeptide Y (NPY) in the arcuate nucleus of the hypothalamus (ARC). However, there is a paucity of data about the possible action of ghrelin on alternative metabolic pathways at this level. Here, we demonstrate that ghrelin elicits a marked upregulation of the hypothalamic mammalian target of rapamycin (mTOR) signaling pathway. Of note, central inhibition of mTOR signaling with rapamycin decreased ghrelin's orexigenic action and normalized the mRNA expression of AgRP and NPY, as well as their key downstream transcription factors, namely cAMP response-element binding protein (pCREB) and forkhead box O1 (FoxO1, total and phosphorylated). Taken together, these data indicate that, in addition to previous reported mechanisms, ghrelin also promotes feeding through modulation of hypothalamic mTOR pathway

Hypothalamic mTOR signaling mediates the orexigenic action of ghrelin

Current evidence suggests that ghrelin, a stomach derived peptide, exerts its orexigenic action through specific modulation of Sirtuin1 (SIRT1)/p53 and AMP-activated protein kinase (AMPK) pathways, which ultimately increase the expression of agouti-related protein (AgRP) and neuropeptide Y (NPY) in the arcuate nucleus of the hypothalamus (ARC). However, there is a paucity of data about the possible action of ghrelin on alternative metabolic pathways at this level. Here, we demonstrate that ghrelin elicits a marked upregulation of the hypothalamic mammalian target of rapamycin (mTOR) signaling pathway. Of note, central inhibition of mTOR signaling with rapamycin decreased ghrelin’s orexigenic action and normalized the mRNA expression of AgRP and NPY, as well as their key downstream transcription factors, namely cAMP response-element binding protein (pCREB) and forkhead box O1 (FoxO1, total and phosphorylated). Taken together, these data indicate that, in addition to previous reported mechanisms, ghrelin also promotes feeding through modulation of hypothalamic mTOR pathway.The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement n° 281854 - the ObERStress project (ML) and 245009 - the Neurofast project (RN, CD and ML), Xunta de Galicia (ML: 10PXIB208164PR; RN: 2010/14), Junta de Andalucía (MTS: P08-CVI-03788), Instituto de Salud Carlos III (ISCIII) (ML: PS09/01880), MINECO co-funded by the FEDER Program of EU (MTS: BFU2011-25021; RN: RyC-2008-02219 and SAF2009-07049; ML: RyC-2007-00211; CD: BFU2011-29102). LM is a recipient of a fellowship from Fundação para a Ciência e Tecnologia (FCT), Portugal (SFRH/BD/65379/2009). CIBER de Fisiopatología de la Obesidad y Nutrición is an initiative of ISCIIIS

Resistin Regulates Pituitary Lipid Metabolism and Inflammation In Vivo and In Vitro

The adipokine resistin is an insulin-antagonizing factor that also plays a regulatory role in inflammation, immunity, food intake, and gonadal function and also regulates growth hormone (GH) secretion in rat adenopituitary cells cultures with the adipokine. Although adipose tissue is the primary source of resistin, it is also expressed in other tissues, including the pituitary. The aim of this study is to investigate the possible action of resistin on the lipid metabolism in the pituitary gland in vivo (rats in two different nutritional status, fed and fast, treated with resistin on acute and a chronic way) and in vitro (adenopituitary cell cultures treated with the adipokine). Here, by a combination of in vivo and in vitro experimental models, we demonstrated that central acute and chronic administration of resistin enhance mRNA levels of the lipid metabolic enzymes which participated on lipolysis and moreover inhibiting mRNA levels of the lipid metabolic enzymes involved in lipogenesis. Taken together, our results demonstrate for the first time that resistin has a regulatory role on lipid metabolism in the pituitary gland providing a novel insight in relation to the mechanism by which this adipokine can participate in the integrated control of lipid metabolism.Sara Borrell Postdoctoral program; BFU 2011 and CIBER Obesidad y Nutricion (Instituto de Salud Carlos Tercero (ISCIII), Ministerio de Ciencia e Innovacion). Juan de la Cierva Program (Ministerio de Educacion y Ciencia)S

Unravelling the role and mechanism of adipokine and gastrointestinal signals in animal models in the nonhomeostatic control of energy homeostasis: Implications for binge eating disorder

Funding information: Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición (CIBERobn); FEDER funds; Xunta de Galicia, Grant/Award Number: ED431, 2017/030; Ministerio de Economía y Competitividad, Grant/Award Number: CD BFU 2017‐87721.Central and peripheral signals regulating energy homeostasis interact tightly with neuronal pathways to modulate the hedonic component of food intake. Dysregulation of these interactions could explain the development of binge eating disorder (BED) and/or obesity and the increasing incidence of food addiction. In this review, we have highlighted the crucial role of peripheral hormones, such as leptin and ghrelin, among others, in these nonhomeostatic pathways. We have also emphasised the relevance of central cannabinoid pathway and lateral hypothalamus, with orexin and melanin-concentrating hormone neurons, as the critical hub controlling motivation and reward. Throughout the manuscript, we have focused on mechanisms learned from animal models of BED/food addiction in order to understand how these peripheral signals can modulate the motivation to eat. Understanding these mechanisms could help us to develop new treatment options for BED and/or obesity.Depto. de Genética, Fisiología y MicrobiologíaFac. de Ciencias BiológicasTRUEpu

Unraveling the Role of Leptin in Liver Function and Its Relationship with Liver Diseases

Since its discovery twenty-five years ago, the fat-derived hormone leptin has provided a revolutionary framework for studying the physiological role of adipose tissue as an endocrine organ. Leptin exerts pleiotropic effects on many metabolic pathways and is tightly connected with the liver, the major player in systemic metabolism. As a consequence, understanding the metabolic and hormonal interplay between the liver and adipose tissue could provide us with new therapeutic targets for some chronic liver diseases, an increasing problem worldwide. In this review, we assess relevant literature regarding the main metabolic effects of leptin on the liver, by direct regulation or through the central nervous system (CNS). We draw special attention to the contribution of leptin to the non-alcoholic fatty liver disease (NAFLD) pathogenesis and its progression to more advanced stages of the disease as non-alcoholic steatohepatitis (NASH). Likewise, we describe the contribution of leptin to the liver regeneration process after partial hepatectomy, the mainstay of treatment for certain hepatic malignant tumorsM.G.N. is recipient of “Juan de la Cierva-Incorporación” fellowship (IJCI-2017-32606) from Ministerio de Ciencia, Innovación y Universidades, Spain. This work was supported by grants from FEDER/Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación (CD: BFU2017-87721) and the TALENTO Program from the Madrid Government (MAFR 2016/T1- BIO-1854). Financial support from the Xunta de Galicia (Centro singular de investigación de Galicia accreditation 2019-2022- ED431G 2019/02) and the European Union (European Regional Development Fund—ERDF), is gratefully acknowledged. Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición (CIBERobn) is an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain, which is supported by FEDER funds (EU)S

Editorial: Role of estrogens as key regulators of energy homeostasis

Depto. de Genética, Fisiología y MicrobiologíaFac. de Ciencias BiológicasTRUEpu