Come to Where Insulin Resistance Is, Come to AMPK Country

The link between smoking and insulin resistance, despite weight loss, is well established; however, the underlying mechanisms remain elusive. A recent article published in Nature Medicine by Wu et al. (2015) reports that nicotine, the main bioactive component of tobacco smoke, activates AMPKα2 in adipocytes, leading to impaired insulin sensitivity

Regulation of NR4A by nutritional status, gender, postnatal development and hormonal deficiency

The NR4A is a subfamily of the orphan nuclear receptors (NR) superfamily constituted by three well characterized members: Nur77 (NR4A1), Nurr1 (NR4A2) and Nor 1 (NR4A3). They are implicated in numerous biological processes as DNA repair, arteriosclerosis, cell apoptosis, carcinogenesis and metabolism. Several studies have demonstrated the role of this subfamily on glucose metabolism, insulin sensitivity and energy balance. These studies have focused mainly in liver and skeletal muscle. However, its potential role in white adipose tissue (WAT), one of the most important tissues involved in the regulation of energy homeostasis, is not well-studied. The aim of this work was to elucidate the regulation of NR4A in WAT under different physiological and pathophysiological settings involved in energy balance such as fasting, postnatal development, gender, hormonal deficiency and pregnancy. We compared NR4A mRNA expression of Nur77, Nurr1 and Nor 1 and found a clear regulation by nutritional status, since the expression of the 3 isoforms is increased after fasting in a leptin-independent manner and sex steroid hormones also modulate NR4A expression in males and females. Our findings indicate that NR4A are regulated by different physiological and pathophysiological settings known to be associated with marked alterations in glucose metabolism and energy status.This work has been supported by grants from Fondo Investigaciones Sanitarias (ST: PI12/02842), Ministerio de Economia y Competitividad (RN: RYC-2008-02219 and BFU2012-35255; MMM: BFU2010-17116), Xunta de Galicia (ML: 10PXIB208164PR and 2012-CP070; RN: EM 2012/039 and 2012-CP069), 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. The research leading to these results has also received funding from the European Community's Seventh Framework Programme under the following grant: ML and RN: FP7/2007-2013: n° 245009: NeuroFASTS

Nicotine' actions on energy balance: friend or foe?

Teixit adipós; Receptors nicotínics; ObesitatTejido adiposo; Receptores nicotínicos; ObesidadAdipose tissue; Nicotinic receptors; ObesityObesity has reached pandemic proportions and is associated with severe comorbidities, such as type 2 diabetes mellitus, hepatic and cardiovascular diseases, and certain cancer types. However, the therapeutic options to treat obesity are limited. Extensive epidemiological studies have shown a strong relationship between smoking and body weight, with non-smokers weighing more than smokers at any age. Increased body weight after smoking cessation is a major factor that interferes with their attempts to quit smoking. Numerous controlled studies in both humans and rodents have reported that nicotine, the main bioactive component of tobacco, exerts a marked anorectic action. Furthermore, nicotine is also known to modulate energy expenditure, by regulating the thermogenic activity of brown adipose tissue (BAT) and the browning of white adipose tissue (WAT), as well as glucose homeostasis. Many of these actions occur at central level, by controlling the activity of hypothalamic neuropeptide systems such as proopiomelanocortin (POMC), or energy sensors such as AMP-activated protein kinase (AMPK). However, direct impact of nicotine on metabolic tissues, such as BAT, WAT, liver and pancreas has also been described. Here, we review the actions of nicotine on energy balance. The relevance of this interaction is interesting, because considering the restricted efficiency of obesity treatments, a possible complementary approach may focus on compounds with known pharmacokinetic profile and pharmacological actions, such as nicotine or nicotinic acetylcholine receptors signaling.Xunta de Galicia (RN: 2016-PG057; ML: 2016-PG068); Ministerio de Economía y Competitividad (MINECO) co-funded by the FEDER Program of EU (RN: RTI2018-099413-B-I00; CD: BFU2017- 87721-P; ML: RTI2018-101840-B-I00; JMF-R and ML: BFU2017- 90578-REDT/Adipoplast); Instituto de Salud Carlos III (JMF-R: PI15–01934); Atresmedia Corporación (RN and ML); Fundación BBVA (RN); “la Caixa” Foundation (ID 100010434), under the agreement LCF/PR/HR19/52160022 (ML); European Foundation for the Study of Diabetes (RN); ERC Synergy Grant-2019-WATCH- 810331 (RN); US Na- tional Institutes of Health (KR: HL084207); the US Department of Vet- erans Affairs (KR: I01BX004249); The University of Iowa Fraternal Order of Eagles Diabetes Research Center (KR). PS-C is recipient of a fel- lowship from Xunta de Galicia (ED481B 2018/050). The CiMUS is sup- ported by the Xunta de Galicia (2016-2019, ED431G/05). CIBER de Fisiopatología de la Obesidad y Nutrición is an initiative of ISCIII

Ghrelin and lipid metabolism: key partners in energy balance

Disclaimer: this is not the definitive version of record of this article. This manuscript has been accepted for publication in "Journal of Molecular Endocrinology", but the version presented here has not yet been copy-edited, formatted or proofed. Consequently, Bioscientifica acepts no responsability for any errors on omissions it may contain. The definitive version is now freely avaliable at doi 10.1677/JME-10-0068[Abstract] Ghrelin, the endogenous ligand of the GH secretagogue receptor, has a pleiotropic role in the modulation of energy balance. Recent evidence has demonstrated that besides its orexigenic role, ghrelin regulates central and peripheral lipid metabolism through specific control of hypothalamic AMP-activated protein kinase (AMPK), a critical metabolic gauge regulating both cellular and whole-body energy homeostasis. In this review, we summarize the new milestones of ghrelin's actions on energy balance, with particular focus on its molecular interaction with hypothalamic AMPK and fatty acid metabolism. Understanding this new metabolic pathway can provide new therapeutic targets for the treatment of obesity and the metabolic syndrome.European Commission; FP7/2007–2013 no. 245009European Commission; FP7/2007–2013; nº 018734Xunta de Gailcia; PS07/12Xunta de Gailcia; PGIDIT06PXIB208063PRXunta de Gailcia; 10PXIB208164PRInstituto de Salud Carlos III; PI051024Instituto de Salud Carlos III;PI070413Instituto de Salud Carlos III; PS09/01880Ministerio de Educacion y Ciencia; RyC-2008-02219Ministerio de Educacion y Ciencia; BFU2008Ministerio de Educacion y Ciencia; RyC-2007-0021

Heterozygous deficiency of endoglin decreases insulin and hepatic triglyceride levels during high fat diet

Endoglin is a transmembrane auxiliary receptor for transforming growth factor-beta (TGF-beta) that is predominantly expressed on proliferating endothelial cells. It plays a wide range of physiological roles but its importance on energy balance or insulin sensitivity has been unexplored. Endoglin deficient mice die during midgestation due to cardiovascular defects. Here we report for first time that heterozygous endoglin deficiency in mice decreases high fat diet-induced hepatic triglyceride content and insulin levels. Importantly, these effects are independent of changes in body weight or adiposity. At molecular level, we failed to detect relevant changes in the insulin signalling pathway at basal levels in liver, muscle or adipose tissues that could explain the insulin-dependent effect. However, we found decreased triglyceride content in the liver of endoglin heterozygous mice fed a high fat diet in comparison to their wild type littermates. Overall, our findings indicate that endoglin is a potentially important physiological mediator of insulin levels and hepatic lipid metabolism

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

Ghrelin

Background: The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor. Increasing evidence supports more complicated and nuanced roles for the hormone, which go beyond the regulation of systemic energy metabolism. Scope of review: In this review, we discuss the diverse biological functions of ghrelin, the regulation of its secretion, and address questions that still remain 15 years after its discovery. Major conclusions: In recent years, ghrelin has been found to have a plethora of central and peripheral actions in distinct areas including learning and memory, gut motility and gastric acid secretion, sleep/wake rhythm, reward seeking behavior, taste sensation and glucose metabolism

Obesity- and gender-dependent role of endogenous somatostatin and cortistatin in the regulation of endocrine and metabolic homeostasis in mice

Somatostatin (SST) and cortistatin (CORT) regulate numerous endocrine secretions and their absence [knockout (KO)-models] causes important endocrine-metabolic alterations, including pituitary dysregulations. We have demonstrated that the metabolic phenotype of single or combined SST/CORT KO-models is not drastically altered under normal conditions. However, the biological actions of SST/CORT are conditioned by the metabolic-status (e.g. obesity). Therefore, we used male/female SST- and CORT-KO mice fed low-fat (LF) or high-fat (HF) diet to explore the interplay between SST/CORT and obesity in the control of relevant pituitary-axes and whole-body metabolism. Our results showed that the SST/CORT role in the control of GH/prolactin secretions is maintained under LF- and HF-diet conditions as SST-KOs presented higher GH/prolactin-levels, while CORT-KOs displayed higher GH- and lower prolactin-levels than controls under both diets. Moreover, the impact of lack of SST/CORT on the metabolic-function was gender- and diet-dependent. Particularly, SST-KOs were more sensitive to HF-diet, exhibiting altered growth and body-composition (fat/lean percentage) and impaired glucose/insulin-metabolism, especially in males. Conversely, only males CORT-KO under LF-diet conditions exhibited significant alterations, displaying higher glucose-levels and insulin-resistance. Altogether, these data demonstrate a tight interplay between SST/CORT-axis and the metabolic status in the control of endocrine/metabolic functions and unveil a clear dissociation of SST/CORT rolesThis work was supported by the following grants: Junta de Andalucía (CTS-1406, BIO-0139), ISCIII-FIS [PI13/00651 and PIE14/00005 (co-funded by European Regional Development Fund/European Social Fund “Investing in your future”)], MINECO (BFU2013–43282-R), “Miguel Servet” Program, CIBERobn and Ayuda Merck Serono 2013S

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

Ghrelin effects on neuropeptides in the rat hypothalamus depend on fatty acid metabolism actions on BSX but not on gender

"This is the peer reviewed version of the following article: Lage, R., Vázquez, M.J., Varela, L., Saha, A.K., Vidal-Puig, A., Nogueiras, R., Diéguez, C. and López, M. (2010), Ghrelin effects on neuropeptides in the rat hypothalamus depend on fatty acid metabolism actions on BSX but not on gender. The FASEB Journal, 24: 2670-2679, which has been published in final form at https://doi.org/10.1096/fj.09-150672. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited."The orexigenic effect of ghrelin is mediated by neuropeptide Y (NPY) and agouti-related protein (AgRP) in the hypothalamic arcuate nucleus (ARC). Recent evidence also indicates that ghrelin promotes feeding through a mechanism involving activation of hypothalamic AMP-activated protein kinase (AMPK) and inactivation of acetyl-CoA carboxylase and fatty acid synthase (FAS). This results in decreased hypothalamic levels of malonyl-CoA, increased carnitine palmitoyltransferase 1 (CPT1) activity, and mitochondrial production of reactive oxygen species. We evaluated whether these molecular events are part of a unique signaling cascade or whether they represent alternative pathways mediating the orexigenic effect of ghrelin. Moreover, we examined the gender dependency of these mechanisms, because recent evidence has proposed that ghrelin orexigenic effect is reduced in female rats. We studied in both genders the effect of ghrelin on the expression of AgRP and NPY, as well as their transcription factors: cAMP response-element binding protein (CREB and its phosphorylated form, pCREB), forkhead box O1 (FoxO1 and its phosphorylated form, pFoxO1), and brain-specific homeobox transcription factor (BSX). In addition, to establish a mechanistic link between ghrelin, fatty acid metabolism, and neuropeptides, we evaluated the effect of ghrelin after blockage of hypothalamic fatty acid β oxidation, by using the CPT1 inhibitor etomoxir. Ghrelin-induced changes in the AMPK-CPT1 pathway are associated with increased levels of AgRP and NPY mRNA expression through modulation of BSX, pCREB, and FoxO1, as well as decreased expression of endoplasmic reticulum (ER) stress markers in a gender-independent manner. In addition, blockage of hypothalamic fatty acid β oxidation prevents the ghrelin-promoting action on AgRP and NPY mRNA expression, also in a gender-independent manner. Notably, this effect is associated with decreased BSX expression and reduced food intake. Overall, our data suggest that BSX integrates changes in neuronal metabolic status with ARC-derived neuropeptides in a gender-independent mannerS