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Obesity and type 2 diabetes are associated with cognitive dysfunction. Because the hypothalamus is implicated in energy balance control and memory disorders, we hypothesized that specific neurons in this brain region are at the interface of metabolism and cognition. Acute obesogenic diet administration in mice impaired recognition memory due to defective production of the neurosteroid precursor pregnenolone in the hypothalamus. Genetic interference with pregnenolone synthesis by Star deletion in hypothalamic POMC, but not AgRP neurons, deteriorated recognition memory independently of metabolic disturbances. Our data suggest that pregnenolone’s effects on cognitive function were mediated via an autocrine mechanism on POMC neurons, influencing hippocampal long-term potentiation. The relevance of central pregnenolone on cognition was also confirmed in metabolically unhealthy patients with obesity. Our data reveal an unsuspected role for POMC neuron-derived neurosteroids in cognition. These results provide the basis for a framework to investigate new facets of POMC neuron biology with implications for cognitive disorders., This work was supported by the Swiss National Science Foundation (no.176206; NCCR Synapsy grant no.185897) to C.S.; the European Research Council (ERC) advanced grant SYNEME to J.C.B.; Instituto de Salud Carlos III (ISCIII)—Fondo Europeo de Desarrollo Regional (FEDER) (PI17/00296), RETICs Oftared (RD16/0008/0014), and Generalitat de Catalunya (2017SGR737) to X.G.; Ministerio de Ciencia e Innovación (BFU2017-83317-P) to D.S.; Ministerio de Economia, Industria y Competitividad, Maria de Maeztu (MDM-2017-0729) to Institut de Neurociencies, Universitat de Barcelona; ISCIII-FEDER (PI14/01126, PI17/01019), the National Institutes of Health (NIA grants 1R01AG056850-01A1, R21AG056974, and R01AG061566), Fundació La Marató de TV3 (20141210), and Generalitat de Catalunya (SLT006/17/00119) to J.F.; ISCIII-FEDER (PI17/00279 and PI20/0042), Fundació La Marató de TV3 (201614.31), and Generalitat de Catalunya (SLT008/18/00127) to A.J.; Plan Nacional de I+D funded by the Agencia Estatal de Investigación (AEI) and FEDER (PID2019-111669RB-I00 and PID2020-115055RB-I00), CIBEREHD, the center grant P50AA011999 Southern California Research Center for ALPD and Cirrhosis funded by NIAAA/NIH, Generalitat de Catalunya (SGR-2017-1112), the European Cooperation in Science & Technology (COST) ACTION CA17112, FUNDACIÓN BBVA (“ER stress-mitochondrial cholesterol axis in obesity-associated insulin resistance and comorbidities”), and Red Nacional 2018-102799-T de Enfermedades Metabólicas y Cáncer and Fundació La Marató de TV3 (201916/31) to J.C.F.-C.; and ERC consolidator grant MITOSENSING (725004), ISCIII-FEDER (PI16/00963), “la Caixa” Foundation (ID100010434) under agreement LCF/PR/HR19/52160016, and CERCA Programme/Generalitat de Catalunya to M.C. D.A. is supported by ISCIII (INT19/00016) and Generalitat de Catalunya PERIS program (SLT006/17/125), A.P. is supported by Hospital Clínic de Barcelona (“Ajut Josep Font”), A.O. is supported by a Miguel Servet contract (CP19/00083) from ISCIII-FEDER, and R.H.-T. is supported by a Marie Skłodowska-Curie Action fellowship (H2020-MSCA-IF) and NEUROPREG (891247). S.R. is a recipient of Juan de la Cierva Formación (FJCI-2016-28911) and Incorporación (IJC2018-037341-I) programs from the Spanish Ministry of Science and Innovation. This work was carried out in part at Esther Koplowitz Centre.

Obesity has now reached pandemic proportions and represents a major socioeconomic and health problem in our societies. Up to now, obesity has been considered a medical issue only in high-income countries, but this disease is now dramatically on the rise in low- and middle-income countries, particularly in urban settings, affecting both adults and the pediatric population [1]. The simplest definition of overweight and obesity is an excessive accumulation of fat due to an imbalance between the energy in and the energy out, and this adiposity represents a risk to health [1]. But the whole picture is more complex than this, and obesity is a marker of a serious metabolic dysregulation that involves several diseases such as type 2 diabetes, cancer, cardiovascular pathologies, and most recently for COVID-19 infection [1,2]. Since the current approaches to combatting obesity and its complications have limited clinical effectiveness, gaining insight into the cellular and molecular basis of obesity could lay the foundations for the development of new strategies to prevent metabolic disruption and to treat this somewhat unaddressed medical issue. In the last few decades, it has been strongly demonstrated that the hypothalamus is the master regulator of energy homeostasis. The hypothalamus contains hormone- and nutrient-sensing nuclei that organize central and peripheral responses for maintaining normal body weight, food intake, energy expenditure, and nutrient partitioning. Within the hypothalamus, specialized sub-populations of neurons are connected to each other and to various extrahypothalamic regions to coordinate energy balance. Evidence has also highlighted the participation of non-neuronal populations (i.e., microglia and astrocytes), and even the interesting cross-talk between these types of brain cells, whose disruption leads to insulin resistance and obesity. In this Special Issue, we report on the most recent insights into the hypothalamic circuitries and pathways involving neurons [3,4,5,6,7], astrocytes [8,9], and microglia [10,11] in obesity development and associated complications. The emerging contribution of astrocyte–neuron [9] and microglia–neuron cross-talks [12] in the hypothalamus and the contribution of microbiota and the gut-brain axis controlling food intake and energy homeostasis [13] are also presented in this Special Issue. info:eu-repo/semantics/publishedVersion

Summary Appropriate cristae remodeling is a determinant of mitochondrial function and bioenergetics and thus represents a crucial process for cellular metabolic adaptations. Here, we show that mitochondrial cristae architecture and expression of the master cristae-remodeling protein OPA1 in proopiomelanocortin (POMC) neurons, which are key metabolic sensors implicated in energy balance control, is affected by fluctuations in nutrient availability. Genetic inactivation of OPA1 in POMC neurons causes dramatic alterations in cristae topology, mitochondrial Ca2+ handling, reduction in alpha-melanocyte stimulating hormone (α-MSH) in target areas, hyperphagia, and attenuated white adipose tissue (WAT) lipolysis resulting in obesity. Pharmacological blockade of mitochondrial Ca2+ influx restores α-MSH and the lipolytic program, while improving the metabolic defects of mutant mice. Chemogenetic manipulation of POMC neurons confirms a role in lipolysis control. Our results unveil a novel axis that connects OPA1 in POMC neurons with mitochondrial cristae, Ca2+ homeostasis, and WAT lipolysis in the regulation of energy balance., Graphical abstract, Highlights • Nutritional state shapes mitochondrial cristae and OPA1 expression in POMC neurons • OPA1 deletion in POMC neurons alters mitochondrial Ca2+ handling and α-MSH release • POMC OPA1-deficient mice show impaired fat lipolysis and metabolic health • Pharmacological restoration of Ca2+ recovered molecular and metabolic alterations, Gómez-Valadés et al. report that mitochondrial cristae dynamically reshape in POMC neurons in response to nutritional state. With genetic targeting, they reveal that the cristae-remodeling protein OPA1 is essential to sustain cristae structure and mitochondrial Ca2+ homeostasis in POMC neurons, ensuring appropriate modulation of α-MSH release, the lipolytic program in adipose tissue and metabolic health.

The crucial role of the hypothalamus in the pathogenesis of obesity is widely recognized, while the precise molecular and cellular mechanisms involved are the focus of intense research. A disrupted endocannabinoid system, which critically modulates feeding and metabolic functions, through central and peripheral mechanisms, is a landmark indicator of obesity, as corroborated by investigations centered on the cannabinoid receptor CB1, considered to offer promise in terms of pharmacologically targeted treatment for obesity. In recent years, novel insights have been obtained, not only into relation to the mode of action of CB receptors, but also CB ligands, non-CB receptors, and metabolizing enzymes considered to be part of the endocannabinoid system (particularly the hypothalamus). The outcome has been a substantial expansion in knowledge of this complex signaling system and in drug development. Here we review recent literature, providing further evidence on the role of hypothalamic endocannabinoids in regulating energy balance and the implication for the pathophysiology of obesity. We discuss how these lipids are dynamically regulated in obesity onset, by diet and metabolic hormones in specific hypothalamic neurons, the impact of gender, and the role of endocannabinoid metabolizing enzymes as promising targets for tackling obesity and related diseases.

[Background]: Functional connectivity alterations in the lateral and medial hypothalamic networks have been associated with the development and maintenance of obesity, but the possible impact on the structural properties of these networks remains largely unexplored. Also, obesity-related gut dysbiosis may delineate specific hypothalamic alterations within obese conditions. We aim to assess the effects of obesity, and obesity and gut-dysbiosis on the structural covariance differences in hypothalamic networks, executive functioning, and depressive symptoms., [Methods]: Medial (MH) and lateral (LH) hypothalamic structural covariance alterations were identified in 57 subjects with obesity compared to 47 subjects without obesity. Gut dysbiosis in the subjects with obesity was defined by the presence of high (n = 28) and low (n = 29) values in a BMI-associated microbial signature, and posthoc comparisons between these groups were used as a proxy to explore the role of obesity-related gut dysbiosis on the hypothalamic measurements, executive function, and depressive symptoms., [Results]: Structural covariance alterations between the MH and the striatum, lateral prefrontal, cingulate, insula, and temporal cortices are congruent with previously functional connectivity disruptions in obesity conditions. MH structural covariance decreases encompassed postcentral parietal cortices in the subjects with obesity and gut-dysbiosis, but increases with subcortical nuclei involved in the coding food-related hedonic information in the subjects with obesity without gut-dysbiosis. Alterations for the structural covariance of the LH in the subjects with obesity and gut-dysbiosis encompassed increases with frontolimbic networks, but decreases with the lateral orbitofrontal cortex in the subjects with obesity without gut-dysbiosis. Subjects with obesity and gut dysbiosis showed higher executive dysfunction and depressive symptoms., [Conclusions]: Obesity-related gut dysbiosis is linked to specific structural covariance alterations in hypothalamic networks relevant to the integration of somatic-visceral information, and emotion regulation., This study has been funded by the Project Grant IRONMET (PI15/01934) from the ISCIII, and the Project ThinkGut (EFA345/19) 65% co-financed by the European Regional Development Fund (ERDF) through the Interreg V-A Spain-France-Andorra program (POCTEFA 2014–2020) (JM Fernández-Real). Partial support was also obtained by the Ministerio de Economia y Competitividad, Spain, reference MTM2015-64465-C2-1-R (ML Calle). O Contreras-Rodriguez is funded by a “PERIS” postdoctoral fellowship (SLT006/17/00236) from the Health Department of the Catalan Government and by a “Miguel Servet” contract (CP20/00165) from the ISCIII. M Arnoriaga-Rodríguez is funded by a predoctoral Rio Hortega contract (CM19/00190) co-funded by European Social Fund “Investigating in your future” from the ISCIII.

The endocannabinoid (eCB) system regulates energy homeostasis and is linked to obesity development. However, the exact dynamic and regulation of eCBs in the hypothalamus during obesity progression remain incompletely described and understood. Our study examined the time course of responses in two hypothalamic eCBs, 2-arachidonoylglycerol (2-AG) and arachidonoylethanolamine (AEA), in male and female mice during diet-induced obesity and explored the association of eCB levels with changes in brown adipose tissue (BAT) thermogenesis and body weight. We fed mice a high-fat diet (HFD), which induced a transient increase (substantial at 7 days) in hypothalamic eCBs followed by a progressive decrease to basal levels with a long-term HFD. This transient rise at early stages of obesity is considered a physiologic compensatory response to BAT thermogenesis, which is activated by diet surplus. The eCB dynamic was sexually dimorphic: hypothalamic eCBs levels were higher in female mice, who became obese at later time points than male. The hypothalamic eCBs time course positively correlated with thermogenesis activation but negatively matched body weight, leptinemia, and circulating eCB levels. Increased expression of eCB-synthetizing enzymes accompanied the transient hypothalamic eCB elevation. Intracerebroventricular injection of eCB did not promote BAT thermogenesis; however, administration of thermogenic molecules, such as central leptin or a peripheral β3-adrenoreceptor agonist, induced a significant increase in hypothalamic eCBs, suggesting a directional link from BAT thermogenesis to hypothalamic eCBs. This study contributes to the understanding of hypothalamic regulation of obesity., We thank Dr. Gemma Fabriàs and Alexandre García from the Research Unit of BioActive Molecules (Institut de Química Avançada de Catalunya, IQAC) for their technical assistance in the analysis of eCB levels. This work was supported by the Ministerio de Economía, Industria y Competitividad (MINECO), Agencia Estatal de Investigación (AEI) and Fondo Europeo de Downloaded from www.jlr.org by guest, on June 3, 2019 Desarrollo Regional (FEDER) (Grants SAF2014-52223-C2-2-R to NC, SAF2017-83813-C3-3-R to NC and RR-R, SAF2017-83813-C3-1-R to DS and LH), the Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y la Nutrición (CIBEROBN) (Grant CB06/03/0001 to DS), the Generalitat de Catalunya (2014SGR465 to DS and NC; 2017SGR152 to JC), Fundació La Marató de TV3 (Grant 87/C/2016 to DS and NC). AF is the recipient of a fellowship from the Agència de Gestió d’Ajuts Universitaris i de la Recerca (AGAUR) in Catalonia.

Maintenance of glucose homeostasis is mandatory for organismal survival. It is accomplished by complex and coordinated interplay between glucose detection mechanisms and multiple effector systems. The brain, in particular homeostatic regions such as the hypothalamus, plays a crucial role in orchestrating such a highly integral response. We review here current understanding of how the hypothalamus senses glucose availability and participates in systemic glucose homeostasis. We provide an update of the relevant signaling pathways and neuronal subsets involved, as well as of the mechanisms modulating metabolic processes in peripheral tissues such as liver, skeletal muscle, fat, and especially the pancreas. We also discuss the relevance of these networks in human biology and prevalent metabolic conditions such as diabetes and obesity.

Treballs Finals de Grau de Química, Facultat de Química, Universitat de Barcelona, Any: 2018, Tutor: Xavier Ariza Piquer, Obesity has become a priority health issue for many governments and organisations such as the WHO, it has gained the status of epidemic and according to the past years trends, the forecasts are not hopeful. The research for anti-obesity drugs has grown in the past years as the percentage of obese people grows globally. A relatively new anti-cancer drug (C75) was tested as anti-cancer drug to rodents, and it was observed that the specimens were showing an anorexigenic behaviour. The molecule was interacting in the hypothalamus reducing the food intake. Since this side effect was discovered many have been the attempts to find derivatives and analogues of C75 focusing on its food intake modulator basal. In this project, we have focused on the synthesis of C75 analogue called (±)-UB-207 that was first reported in 2012. The novelty of the present work consists in modifying the initial synthetic route in order to simplify the obtainment of the pure derivative

Treballs Finals de Grau de Química, Facultat de Química, Universitat de Barcelona, Any: 2018, Tutor: Xavier Ariza Piquer Obesity has become a priority health issue for many governments and organisations such as the WHO, it has gained the status of epidemic and according to the past years trends, the forecasts are not hopeful. The research for anti-obesity drugs has grown in the past years as the percentage of obese people grows globally. A relatively new anti-cancer drug (C75) was tested as anti-cancer drug to rodents, and it was observed that the specimens were showing an anorexigenic behaviour. The molecule was interacting in the hypothalamus reducing the food intake. Since this side effect was discovered many have been the attempts to find derivatives and analogues of C75 focusing on its food intake modulator basal. In this project, we have focused on the synthesis of C75 analogue called (±)-UB-207 that was first reported in 2012. The novelty of the present work consists in modifying the initial synthetic route in order to simplify the obtainment of the pure derivative

Interactions between the hypothalamus and non-homeostatic regions may contribute to explain the difficulty to lose weight in obesity, an assumption never tested in human longitudinal studies. We investigated whether the functional connectivity between the medial and lateral hypothalamus (MH and LH) and corticostriatal regions differs between individuals with excess weight (n = 42) and normal weight (n = 39) using a seed-based resting-state approach. In addition, we examined the longitudinal association between functional connectivity and weight loss in a 3-month follow-up diet. Results showed that participants with excess weight had increased connectivity between the MH and the striatum and subgenual anterior cingulate cortex, and decreased connectivity with the middle frontal gyrus, and the bed nucleus of the stria terminalis (BNST), as well as a decreased connectivity between the LH and the cerebellum. Decreased connectivity between the MH and the posterior part of the BNST, and between the LH and the cerebellar cortex, predicted a greater percentage of weight loss. Functional connectivity measures explained 36% of the 3-month weight change among individuals with excess weight. We conclude that altered functional connectivity between homeostatic-hypothalamic regions and non-homeostatic corticostriatal and cerebellar regions is linked to obesity and difficulty to lose weight.

SUMMARY 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 (glucose-regulated 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., In Brief The brain senses lipids, such as fatty acids, and modifies energy metabolism accordingly. However, it is unclear whether other lipid species may be involved. Contreras et al. now demonstrate that ceramides regulate energy balance through the induction of hypothalamic lipotoxicity and modulation of endoplasmic reticulum functionality. This leads to changes in sympathetic tone and brown adipose tissue (BAT)-induced thermogenesis, impacting body weight.

[eng] Previous studies have reported the importance of carnitine palmitoyltransferase (CPT) 1A as an essential part of downstream ghrelin signaling in the central nervous system (CNS) for the control of food intake. Lipid metabolism in the ventromedial hypothalamus (VMH) has emerged as a crucial pathway in the regulation of feeding and energy homeostasis. However, the relationship between changes in CPT1A activity and the intracellular downstream effectors in the VMH that contribute to appetite modulation is not fully understood, nor its possible involvement in central extra-hypothalamic functions of ghrelin. In this work, we examine the effect of long-term expression of a permanently activated CPT1A isoform (CPT1AM) by using an adeno-associated viral vector, injected into the VMH of rats. CPT1AM overexpression produces a sustained increase in food intake which leads to overweight. Mechanistically, CPT1AM alters the lipidomic profile of mediobasal hypothalamus, provoking an increase in ceramides and sphingolipids and a decrease in phospholipids. Furthermore, we detect increased vesicular y-aminobutyric acid transporter (VGAT) and reduced vesicular glutamate transporter 2 (VGLUT2) expressions. These changes are noteworthy, since both GABA and glutamate have been proposed to be mediators in food intake control. This signature led us to assess the effect of ghrelin in GABAergic neurons. Ghrelin reduces fatty acid oxidation, mitochondrial respiration and mitochondrial reactive oxygen species formation in GT1-7 cells. Moreover, ghrelin produces a reduction in GABA release from primary cortical neurons which is blocked by both pharmacological and genetic inhibition of CPT1A. In addition, ghrelin produces a reduction in: (1) mitochondrial oxygen consumption, (2) citrate and a-ketoglutarate cellular content and (3) GABA shunt connecting TCA cycle and releasable GABA pool. Taken together, these observations indicate that CPT1A contributes to the regulation of feeding by modulating the expression of neurotransmitter transporters and lipid components that influence the orexigenic pathways in VMH. Moreover, it seems that ghrelin and changes in CPT1A activity modulate mitochondrial function, yielding changes in GABA metabolism, which affect eventually to GABAergic neurotransmission., [cat] Estudis previs havien destacat la importància de la carnitina palmitoïltransferasa (CPT) 1A com a part essencial de la senyalització de la grelina al sistema nerviós central (SNC) per al control de la ingesta alimentària. El metabolisme lipídic en el nucli ventromedial de l'hipotàlem (VMH) ha emergit com una via crucial per a la regulació de la ingesta i l'homeòstasi energètica. Això no obstant, la relació entre els canvis en l'activitat de la CPT1A i els efectors intrace•ulars subjacents en el VMH que contribueixen a la modulació de la gana no són totalment compresos, com tampoc la seva involucració en les funcions centrals extrahipotalàmiques de la grelina. En aquest treball, hem examinat l'efecte a llarg termini de l'expressió d'una isoforma mutada permanentment activa de la CPT1A (CPT1AM), fent ús d'un vector víric adeno-associat, injectat en el VMH de rates. La sobreexpressió de la CPT1AM produeix un augment sostingut de la ingesta alimentària que hi promou sobrepès. En la descripció mecanística, la CPT1AM altera el perfil lipidòmic del hipotàlem mediobasal, induint-hi un augment de ceramides i esfingolípids i alhora una reducció en fosfolípids. A més a més, hem detectat un augment en les expressions del transportador vesicular de l'àcid y-aminobutíric (GABA) (VGAT, en les seves sigles en anglès) i una reducció del transportador vesicular de glutamat 2 (VGLUT2, en les seves sigles en anglès). Aquests canvis són destacables, ja que tant GABA como glutamat han sigut proposats com a mediadors en el control de la ingesta alimentària. Aquestes observacions ens dugueren a estudiar l'efecte de la grelina en neurones GABAèrgiques. La grelina redueix l'oxidació d'àcids grassos, la respiració mitocondrial i la formació d'espècies reactives d'oxigen en cèl•lules GT1-7. D'afegitó, la grelina produeix una reducció en l'alliberament de GABA de neurones corticals primàries, la qual cosa és blocada tant per inhibició genètica i farmacològica de la CPT1A. A més a més, la grelina hi produeix una reducció: (1) del consum mitocondrial d'oxigen, (2) del contingut cel•lular de citrat i d'a-cetoglutarat i (3) de la via de desviació de GABA que connecta el cicle dels àcids tricarboxílics i el contingut alliberable de GABA. En conjunt, aquestes observacions indiquen que la CPT1A contribueix a la regulació de la ingesta amb la modulació de l'expressió de transportadors involucrats en la neurotransmissió i la modulació de components lipídics que influencien les vies orexigèniques del VMH. A més a més, sembla que la grelina i els canvis en l'activitat CPT1A modulen la funció mitocondrial, obtenint-ne canvis al metabolisme del GABA, que afecten en darrera instància a la neurotransmissió GABAèrgica.

The hypothalamus is a crucial central nervous system area controlling appetite, body weight and metabolism. It consists in multiple neuronal types that sense, integrate and generate appropriate responses to hormonal and nutritional signals partly by fine-tuning the expression of specific batteries of genes. However, the mechanisms regulating these neuronal gene programmes in physiology and pathophysiology are not completely understood. MicroRNAs (miRNAs) are key regulators of gene expression that recently emerged as pivotal modulators of systemic metabolism. In this article we will review current evidence indicating that miRNAs in hypothalamic neurons are also implicated in appetite and whole-body energy balance control.

[cat]La elevada incidencia de la obesidad y las enfermedades relacionadas han convertido en una prioridad el estudio de los mecanismos destinados a controlar la ingesta y el gasto calórico. Ambos procesos están regulados por las interacciones bidireccionales entre el sistema nervioso central y los órganos periféricos, las cuales permiten crear un mapa del estado energético del organismo y responder en consecuencia ajustando tanto el consumo de alimentos como el gasto de energía. El hipotálamo es una parte del sistema nervioso central con un papel protagonista en el control de la homeostasis energética. Es una estructura integradora de señales centrales y periféricas implicada en la regulación de varios procesos, entre otros, el apetito. Durante los últimos años, múltiples estudios han tratado de profundizar en los mecanismos moleculares que, en el hipotálamo, controlan la expresión de los neuropéptidos y neuromoduladores encargados de regular la ingesta. Como resultado se ha demostrado el papel clave que juega el metabolismo de los ácidos grasos en estos procesos. Concretamente, se ha propuesto que moléculas como el malonil-CoA derivado de la glucosa, o los aciles-CoA de cadena larga (LCFA-CoA, long chain fatty acyl-CoA) actúan como señales intracelulares de saciedad regulando el apetito. El enzima carnitina palmitoiltransferasa (CPT) 1, cataliza la entrada de LCFA-CoA al interior de la mitocondria, y es el principal regulador de la oxidación de ácidos grasos. A su vez, su actividad se encuentra inhibida por el primer intermediario de la lipogénesis, el malonil-CoA, lo que permite mantener un equilibrio entre la síntesis y la oxidación de las grasas. En esta Tesis se ha estudiado el efecto que la modulación de CPT1 en el hipotálamo tiene sobre la ingesta de alimentos. Para ello se han utilizado dos aproximaciones experimentales diferentes. En primer lugar se ha sobre expresado una isoforma permanentemente activa del enzima (CPT1AM) en el núcleo ventromedial del hipotálamo. En segundo lugar se ha estudiado el efecto de la administración central del compuesto anorexigénico C75 que, una vez activado a C75-CoA, actúa como potente inhibidor de CPT1. Los resultados obtenidos demuestran que la sobre-expresión de CPT1AM en el hipotálamo causa inicialmente hiperfagia y, en un estado posterior, resistencia a la insulina, intolerancia a la glucosa e hiperglucemia. Por otro lado, la inhibición de CPT1 en el hipotálamo tras el tratamiento con C75 produce una disminución de la ingesta y una pérdida de peso aportando nuevas pistas sobre el mecanismo de acción central de C75. Tomados en conjunto, estos resultados confirman el importante papel que el enzima CPT1 juega en la regulación del apetito. Asimismo, aportan nuevos datos sobre los mecanismos centrales que modulan el metabolismo glucídico. Por otro lado demuestran que la inhibición de CPT1 a nivel central se deriva en una disminución de la ingesta resaltando la importancia de este enzima como diana terapéutica para el tratamiento de la obesidad., [eng] “Role of hypothalamic carnitine palmotoyltransferase 1A in the control of food intake” Neutral energy balance permits body weight stability and prevents the emergence of diseases such as obesity and Type 2 Diabetes. Central nervous system (CNS) and more specifically the hypothalamus, has a key role in the regulation of homeostatic mechanisms that control food consumption. In response to changes in global energy status, hypothalamic neurons alter the expression of neuropeptides in order to adjust energy intake and expenditure. It is unclear how the expression of these molecules is regulated; however recent studies highlight fatty acid metabolism as a key pathway in hypothalamic control of feeding. Several studies have demonstrated that modulation of fatty acid metabolic enzymes can regulate feeding behaviour by altering the hypothalamic pool of malonyl-CoA and/or long chain fatty acid-CoA (LCFA-CoA), suggesting that these metabolites are signals of nutrient status able to adjust not only food intake but also energy expenditure and glucose production. Malonyl-CoA, derived from glucose metabolism, is not only the first intermediate in fatty acid synthesis but also has a role in the maintenance of balance between de novo synthesis of fatty acids and its oxidation. Malonyl-CoA is the physiological inhibitor of carnitine palmitoyltransferase 1 (CPT1), enzyme that catalyses the first step in the transport of LCFA-CoA from the cytoplasm into the mitochondria for their b-oxidation. In the present study we analysed the role of hypothalamic CPT1A in the regulation of food intake. To this aim we used two experimental strategies. On the one hand, we over-expressed a permanently active form of CPT1A (CPT1AM: malonyl-CoAinsensitive-CPT1A) in the VMH of rats and studied its effect on food intake, body weight and glucose metabolism. On the other hand we studied the molecular mechanism by which compound C75 produces anorexia and a reduction in body weight, focusing our attention on its effect on hypothalamic CPT1 activity. Our results show that a long-term increase in CPT1AM activity in the VMH of rats leads to central and peripheral responses producing hyperphagia, overweight, insulin resistance and glucose intolerance. On the other hand we demonstrated that only (+)-C75 enantiomer inhibits CPT1 activity and its central administration produces a reduction in food intake and body weight. Altogether these data emphasizes the role of hypothalamic CPT1 in the maintenance of energy homeostasis and highlights its inhibitors as good candidates for the treatment of obesity and related diseases.

Lipid metabolism in the ventromedial hypothalamus (VMH) has emerged as a crucial pathway in the regulation of feeding and energy homeostasis. Carnitine palmitoyltransferase (CPT) 1A is the rate-limiting enzyme in mitochondrial fatty acid β-oxidation and it has been proposed as a crucial mediator of fasting and ghrelin orexigenic signalling. However, the relationship between changes in CPT1A activity and the intracellular downstream effectors in the VMH that contribute to appetite modulation is not fully understood. To this end, we examined the effect of long-term expression of a permanently activated CPT1A isoform by using an adeno-associated viral vector injected into the VMH of rats. Peripherally, this procedure provoked hyperghrelinemia and hyperphagia, which led to overweight, hyperglycemia and insulin resistance. In the mediobasal hypothalamus (MBH), long-term CPT1AM expression in the VMH did not modify acyl-CoA or malonyl-CoA levels. However, it altered the MBH lipidomic profile since ceramides and sphingolipids increased and phospholipids decreased. Furthermore, we detected increased vesicular γ-aminobutyric acid transporter (VGAT) and reduced vesicular glutamate transporter 2 (VGLUT2) expressions, both transporters involved in this orexigenic signal. Taken together, these observations indicate that CPT1A contributes to the regulation of feeding by modulating the expression of neurotransmitter transporters and lipid components that influence the orexigenic pathways in VMH. © 2014 Mera et al.

Objective:Carnitine palmitoyltransferase 1C (CPT1C) is implicated in central regulation of energy homeostasis. Our aim was to investigatewhether CPT1C in the ventromedial nucleus of the hypothalamus (VMH) is involved in the activation of brown adipose tissue (BAT) thermogenesisin the early stages of diet-induced obesity.Methods:CPT1C KO and wild type (WT) mice were exposed to short-term high-fat (HF) diet feeding or to intracerebroventricular leptinadministration and BAT thermogenesis activation was evaluated. Body weight, adiposity, food intake, and leptinemia were also assayed.Results:Under 7 days of HF diet, WT mice showed a maximum activation peak of BAT thermogenesis that counteracted obesity development,whereas this activation was impaired in CPT1C KO mice. KO animals evidenced higher body weight, adiposity, hyperleptinemia, ER stress, anddisrupted hypothalamic leptin signaling. Leptin-induced BAT thermogenesis was abolished in KO mice. These results indicate an earlier onsetleptin resistance in CPT1C KO mice. Since AMPK in the VMH is crucial in the regulation of BAT thermogenesis, we analyzed if CPT1C was adownstream factor of this pathway. Genetic inactivation of AMPK within the VMH was unable to induce BAT thermogenesis and body weight lossin KO mice, indicating that CPT1C is likely downstream AMPK in the central mechanism modulating thermogenesis within the VMH. Quiteopposite, the expression of CPT1C in the VMH restored the phenotype.Conclusion:CPT1C is necessary for the activation of BAT thermogenesis driven by leptin, HF diet exposure, and AMPK inhibition within the VMH.This study underscores the importance of CPT1C in the activation of BAT thermogenesis to counteract diet-induced obesity This work was supported by the Ministerio de Economía, Industria y Competitividad (MINECO), Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) (Grants SAF2014-52223-C2-2-R to NC, SAF2017-83813-C3-3-R to NC and RR-R, SAF2014-52223-C2-1-R to DS, SAF2017-83813-C3-1-R to DS and LH, SAF2015-71026-R to ML, TEC2014-51903-R to MV and XP, and Ramón y Cajal RYC-2010-07434 to XP), the Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y la Nutrición (CIBEROBN) (Grant CB06/03/0001 to DS), the Generalitat de Catalunya (2014SGR465 to DS and NC, 2017SGR1384 to MV and XP), Fundació La Marató de TV3 (Grant 87/C/2016 to DS and NC), and by Projectes de Recerca per a investigadors novells (2015) to RR-R. AF is the recipient of a fellowship from the Agència de Gestió d’Ajuts Universitaris i de la Recerca (AGAUR) in Catalonia SI