Circulating Irisin Levels Are Not Regulated by Nutritional Status, Obesity, or Leptin Levels in Rodents

Irisin is a cleaved and secreted fragment of fibronectin type III domain containing 5 (FNDC5) that is mainly released by skeletal muscle and was proposed to mediate the beneficial effects of exercise on metabolism. In the present study we aim to investigate the regulation of the circulating levels of irisin in obese animal models (diet-induced obese (DIO) rats and leptin-deficient (ob/ob) mice), as well as the influence of nutritional status and leptin. Irisin levels were measured by Enzyme-Linked Immunosorbent Assay (ELISA) and Radioimmunoassay (RIA). Serum irisin levels remained unaltered in DIO rats and ob/ob mice. Moreover, its circulating levels were also unaffected by fasting, leptin deficiency, and exogenous leptin administration in rodents. In spite of these negative results we find a negative correlation between irisin and insulin in DIO animals and a positive correlation between irisin and glucose under short-term changes in nutritional status. Our findings indicate that serum irisin levels are not modulated by different physiological settings associated to alterations in energy homeostasis. These results suggest that in rodents circulating levels of irisin are not involved in the pathophysiology of obesity and could be unrelated to metabolic status; however, further studies should clarify its precise role in states of glucose homeostasis imbalance.Xunta de GaliciaIDISGobierno de España/Ministerio de Economía y CompetitividadInstituto de Salud Carlos III (ISCIII

Circulating irisin levels are not regulated by nutritional status, obesity, or leptin levels in rodents

Irisin is a cleaved and secreted fragment of fibronectin type III domain containing 5 (FNDC5) that is mainly released by skeletal muscle and was proposed to mediate the beneficial effects of exercise on metabolism. In the present study we aim to investigate the regulation of the circulating levels of irisin in obese animal models (diet-induced obese (DIO) rats and leptin-deficient (ob/ob) mice), as well as the influence of nutritional status and leptin. Irisin levels were measured by Enzyme-Linked Immunosorbent Assay (ELISA) and Radioimmunoassay (RIA). Serum irisin levels remained unaltered in DIO rats and ob/ob mice. Moreover, its circulating levels were also unaffected by fasting, leptin deficiency, and exogenous leptin administration in rodents. In spite of these negative results we find a negative correlation between irisin and insulin in DIO animals and a positive correlation between irisin and glucose under short-term changes in nutritional status. Our findings indicate that serum irisin levels are not modulated by different physiological settings associated to alterations in energy homeostasis. These results suggest that in rodents circulating levels of irisin are not involved in the pathophysiology of obesity and could be unrelated to metabolic status; however, further studies should clarify its precise role in states of glucose homeostasis imbalance.Mar Quiñones is a recipient of a Postdoctoral Fellowship from Galician Government (Xunta de Galicia ED481B2014/039-0). Cintia Folgueira is funded by IDIS. Estrella Sánchez-Rebordelo is a fellowship of the Ministerio de Economia y Competitividad (ref: BES-2013-062796). Omar Al-Massadi is funded by the ISCIII/SERGAS thought a research contract “Sara Borrell” (CD14/00091)S

Modulation of hypothalamic AMPK phosphorylation by olanzapine controls energy balance and body weight

[Background]: Second-generation antipsychotics (SGAs) are a mainstay therapy for schizophrenia. SGA-treated patients present higher risk for weight gain, dyslipidemia and hyperglycemia. Herein, we evaluated the effects of olanzapine (OLA), widely prescribed SGA, in mice focusing on changes in body weight and energy balance. We further explored OLA effects in protein tyrosine phosphatase-1B deficient (PTP1B-KO) mice, a preclinical model of leptin hypersensitivity protected against obesity.[Methods]: Wild-type (WT) and PTP1B-KO mice were fed an OLA-supplemented diet (5 mg/kg/day, 7 months) or treated with OLA via intraperitoneal (i.p.) injection or by oral gavage (10 mg/kg/day, 8 weeks). Readouts of the crosstalk between hypothalamus and brown or subcutaneous white adipose tissue (BAT and iWAT, respectively) were assessed. The effects of intrahypothalamic administration of OLA with adenoviruses expressing constitutive active AMPKα1 in mice were also analyzed.[Results]: Both WT and PTP1B-KO mice receiving OLA-supplemented diet presented hyperphagia, but weight gain was enhanced only in WT mice. Unexpectedly, all mice receiving OLA via i.p. lost weight without changes in food intake, but with increased energy expenditure (EE). In these mice, reduced hypothalamic AMPK phosphorylation concurred with elevations in UCP-1 and temperature in BAT. These effects were also found by intrahypothalamic OLA injection and were abolished by constitutive activation of AMPK in the hypothalamus. Additionally, OLA i.p. treatment was associated with enhanced Tyrosine Hydroxylase (TH)-positive innervation and less sympathetic neuron-associated macrophages in iWAT. Both central and i.p. OLA injections increased UCP-1 and TH in iWAT, an effect also prevented by hypothalamic AMPK activation. By contrast, in mice fed an OLA-supplemented diet, BAT thermogenesis was only enhanced in those lacking PTP1B. Our results shed light for the first time that a threshold of OLA levels reaching the hypothalamus is required to activate the hypothalamus BAT/iWAT axis and, therefore, avoid weight gain.[Conclusion]: Our results have unraveled an unexpected metabolic rewiring controlled by hypothalamic AMPK that avoids weight gain in male mice treated i.p. with OLA by activating BAT thermogenesis and iWAT browning and a potential benefit of PTP1B inhibition against OLA-induced weight gain upon oral treatment.This work was funded by grants PID-2021-122766OB-100 (to AMV) and PID2019-104399RB-I00 (to GS) funded by Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación /10.13039/501100011033 and “ERDF A way of making Europe” by the European Union. We also acknowledge grants H2020 Marie Sklodowska-Curie ITN-TREATMENT (Grant Agreement 721236, European Commission), S2017/BMD-3684 (Comunidad de Madrid, Spain), Fundación Ramón Areces (Spain) and CIBERdem (ISCIII, Spain) to AMV. JWE was funded by the Swedish Diabetes Foundation and the Novo Nordisk Foundation (NNF20OC0063864). VF was a recipient of a contract from ITN-TREATMENT and is currently a PhD fellow from the Portuguese Foundation for Science and Technology (FCT, Portugal)/ERDF (2020.08388.BD). CF was awarded with Sara Borrell contract (CD19/00078, ISCIII, Spain)

Comparative secretome analysis of rat stomach under different nutritional status

The fact that gastric surgery is at the moment the most effective treatment to fight against obesity highlights the relevance of gastric derived proteins as potential targets to treat this pathology. Taking advantage of a previously established gastric explant model for endocrine studies, the proteomic analysis of gastric secretome was performed. To validate this gastric explant system for proteomic analysis, the identification of ghrelin, a classical gastric derived peptide, was performed by MS. In addition, the differential analysis of gastric secretomes under differential nutritional status (control feeding vs fasting vs re-feeding) was performed. The MS identified proteins are showed in the present manuscript. The data supplied in this article is related to the research article entitled "Comparative secretome analysis of rat stomach under different nutritional status" (L.L. Senin, A. Roca-Rivada, C. Castelao, J. Alonso, C. Folgueira, F.F. Casanueva, M. Pardo, L.M. Seoane Comparative secretome analysis of rat stomach under different nutritional status J. Proteomics (2015))

Hypothyroidism confers tolerance to cerebral malaria

The modulation of the host’s metabolism to protect tissue from damage induces tolerance to infections increasing survival. Here, we examined the role of the thyroid hormones, key metabolic regulators, in the outcome of malaria. Hypothyroidism confers protection to experimental cerebral malaria by a disease tolerance mechanism. Hypothyroid mice display increased survival after infection with Plasmodium berghei ANKA, diminishing intracranial pressure and brain damage, without altering pathogen burden, blood-brain barrier disruption, or immune cell infiltration. This protection is reversed by treatment with a Sirtuin 1 inhibitor, while treatment of euthyroid mice with a Sirtuin 1 activator induces tolerance and reduces intracranial pressure and lethality. This indicates that thyroid hormones and Sirtuin 1 are previously unknown targets for cerebral malaria treatment, a major killer of children in endemic malaria areas.This work was funded by grants SAF2017-83289-R to S.A. and A.A., SAF2017-90604REDT to A.A. supported by the The European Regional Development Fund (FEDER) and BIO2016-77430-R to J.M.B. from the Ministerio de Economía y Competitividad; B2017/BMD-3724 to S.A. and A.A. from the Comunidad de Madrid; and CIBERONC CB/16/00228 to A.A. from the Instituto de Salud Carlos III

ANGPTL-4 is Associated with Obesity and Lipid Profile in Children and Adolescents

Angiopoietin-like protein 4 (ANGPTL-4) regulates lipidic metabolism and affects energy homeostasis. However, its function in children with obesity remains unknown. We investigated plasma ANGPTL-4 levels in children and its relationship with body mass index (BMI) and different lipidic parameters such as free fatty acids (FFA). Plasma ANGPTL-4 levels were analyzed in two different cohorts. In the first cohort (n = 150, age 3–17 years), which included children with normal weight or obesity, we performed a cross-sectional study. In the second cohort, which included only children with obesity (n = 20, age 5–18 years) followed up for two years after an intervention for weight loss, in which we performed a longitudinal study measuring ANGPTL-4 before and after BMI-loss. In the cross-sectional study, circulating ANGPTL-4 levels were lower in children with obesity than in those with normal weight. Moreover, ANGPTL-4 presented a negative correlation with BMI, waist circumference, weight, insulin, homeostasis model assessment of insulin resistance index (HOMA index), triglycerides, and leptin, and a positive correlation with FFA and vitamin-D. In the longitudinal study, the percent change in plasma ANGPTL-4 was correlated with the percent change in FFA, total-cholesterol and high-density lipoprotein cholesterol. This study reveals a significant association of ANGPTL-4 with pediatric obesity and plasma lipid profileThis research was funded by INSTITUTO DE SALUD CARLOS III cofounded by FEDER, grants number PI18/00998, PI15/01272, PI11/02042, PI16/01301, and PI16/00871, and FUNDACIÓN MUTUA MADRILEÑAS

Melanin-Concentrating Hormone acts through hypothalamic kappa opioid system and p70S6K to stimulate acute food intake.

Melanin-Concentrating Hormone (MCH) is one of the most relevant orexigenic factors specifically located in the lateral hypothalamic area (LHA), with its physiological relevance demonstrated in studies using several genetically manipulated mice models. However, the central mechanisms controlling MCH-induced hyperphagia remain largely uncharacterized. Here, we show that central injection of MCH in mice deficient for kappa opoid receptor (k-OR) failed to stimulate feeding. To determine the hypothalamic area responsible for this MCH/k-OR interaction, we performed virogenetic studies and found that downregulation of k-OR by adeno-associated viruses (shOprk1-AAV) in LHA, but not in other hypothalamic nuclei, was sufficient to block MCH-induced food intake. Next, we sought to investigate the molecular signaling pathway within the LHA that mediates acute central MCH stimulation of food intake. We found that MCH activates k-OR and that increased levels of phosphorylated extracellular signal regulated kinase (ERK) are associated with downregulation of phospho-S6 Ribosomal Protein. This effect was prevented when a pharmacological inhibitor of k-OR was co-administered with MCH. Finally, the specific activation of the direct upstream regulator of S6 (p70S6K) in the LHA attenuated MCH-stimulated food consumption. Our results reveal that lateral hypothalamic k-OR system modulates the orexigenic action of MCH via the p70S6K/S6 pathway

Neutrophil infiltration regulates clock-gene expression to organize daily hepatic metabolism.

Liver metabolism follows diurnal fluctuations through the modulation of molecular clock genes. Disruption of this molecular clock can result in metabolic disease but its potential regulation by immune cells remains unexplored. Here, we demonstrated that in steady state, neutrophils infiltrated the mouse liver following a circadian pattern and regulated hepatocyte clock-genes by neutrophil elastase (NE) secretion. NE signals through c-Jun NH2-terminal kinase (JNK) inhibiting fibroblast growth factor 21 (FGF21) and activating Bmal1 expression in the hepatocyte. Interestingly, mice with neutropenia, defective neutrophil infiltration or lacking elastase were protected against steatosis correlating with lower JNK activation, reduced Bmal1 and increased FGF21 expression, together with decreased lipogenesis in the liver. Lastly, using a cohort of human samples we found a direct correlation between JNK activation, NE levels and Bmal1 expression in the liver. This study demonstrates that neutrophils contribute to the maintenance of daily hepatic homeostasis through the regulation of the NE/JNK/Bmal1 axis.BGT and MC were fellows of the FPI: Severo Ochoa CNIC program (SVP-2013–067639) and (BES-2017–079711) respectively. IN was funded by EFSD/Lilly grants (2017 and 2019), the CNIC IPP FP7 Marie Curie Programme (PCOFUND-2012–600396), EFSD Rising Star award (2019), JDC-2018-Incorporación (MIN/JDC1802). T-L was a Juan de la Cierva fellow (JCI2011–11623). C.F has a Sara Borrell contract (CD19/00078). RJD is an Investigator of the Howard Hughes Medical Institute. This work was funded by the following grants to GS: funding from the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement n˚ ERC 260464, EFSD/Lilly European Diabetes Research Programme Dr Sabio, 2017 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation (Investigadores-BBVA-2017) IN[17] _BBM_BAS_0066, MINECO-FEDER SAF2016-79126-R and PID2019-104399RB-I00 , EUIN201785875, Comunidad de Madrid IMMUNOTHERCAN-CM S2010/BMD-2326 and B2017/BMD-3733 and Fundación AECC AECC PROYE19047SABI and AECC: INVES20026LEIV to ML. MM was funded by ISCIII and FEDER PI16/01548 and Junta de Castilla y León GRS 1362/A/16 and INT/M/17/17 and JL-T by Junta de Castilla y León GRS 1356/A/16 and GRS 1587/A/17. The study was additionally funded by MEIC grants to ML (MINECO-FEDER-SAF2015-74112-JIN) AT-L (MINECO-FEDERSAF2014-61233-JIN), RJD: Grant DK R01 DK107220 from the National Institutes of Health. AH: (SAF2015-65607-R). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovación y Universidades (MCNU) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015–0505).S

Methionine adenosyltransferase 1a antisense oligonucleotides activate the liver-brown adipose tissue axis preventing obesity and associated hepatosteatosis

Altered methionine metabolism is associated with weight gain in obesity. The methionine adenosyltransferase (MAT), catalyzing the first reaction of the methionine cycle, plays an important role regulating lipid metabolism. However, its role in obesity, when a plethora of metabolic diseases occurs, is still unknown. By using antisense oligonucleotides (ASO) and genetic depletion of Mat1a, here, we demonstrate that Mat1a deficiency in diet-induce obese or genetically obese mice prevented and reversed obesity and obesity-associated insulin resistance and hepatosteatosis by increasing energy expenditure in a hepatocyte FGF21 dependent fashion. The increased NRF2-mediated FGF21 secretion induced by targeting Mat1a, mobilized plasma lipids towards the BAT to be catabolized, induced thermogenesis and reduced body weight, inhibiting hepatic de novo lipogenesis. The beneficial effects of Mat1a ASO were abolished following FGF21 depletion in hepatocytes. Thus, targeting Mat1a activates the liver-BAT axis by increasing NRF2-mediated FGF21 secretion, which prevents obesity, insulin resistance and hepatosteatosis. High methionine and S-adenosylmethionine serum levels are related with obesity. Here the authors show that knockdown of methionine adenosyltransferase by using antisense oligonucleotides provides beneficial effects in obesity and comorbidities.This work was supported by Ayudas para apoyar grupos de investigacion del sistema Universitario Vasco (IT971-16) and MCIU/AEI/FEDER, UE (RTI2018-095134-B-100) (to P.A.), (RTI2018-099413-B-I00 and RED2018-102379-T) (to R.N.), PID2020119486RB-100 (to M.V.R.) and (RTI2018-096759-A-100) (to T.C.D). EFSD/Lilly European Diabetes Research Program, MICIU (PID2019-104399RB-I00), Fundacion AECC PROYE19047SABI, and Comunidad de Madrid IMMUNOTHERCAN-CM B2017/BMD-3733 (to G.S.). La CAIXA Foundation LCF/PR/HP17/52190004, MINECO-FEDER SAF2017-87301-R, AYUDAS FUNDACION BBVA A EQUIPOS DE INVESTIGACION CIENTIFICA UMBRELLA 2018 and AECC Scientific Foundation, grant name: Rare Cancers 2017 (to M.L.M.-C.). AECC Scientific Foundation (to T.C.D.). Xunta de Galicia 2020-PG015 (to R.N.) Gilead Sciences International Research Scholars Program in Liver Disease (to M.V.R.). Personal fellows: E.P.F. was awarded with Juan de la Cierva-Formacion, FJC2018-035449-I. C.F. was awarded with Sara Borrell (CD19/00078). CIC bioGUNE thanks MCIU for the Severo Ochoa Excellence Accreditation (SEV-2016-0644). The authors thank Dr. Manuel Lafitas laboratory (Getxo, Bizkaia, Spain) for his valuable help in the analysis of biochemical parameters