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1.
Nat Commun ; 11(1): 5145, 2020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-33051459

RESUMO

Based on studies in mice, leptin was expected to decrease body weight in obese individuals. However, the majority of the obese are hyperleptinemic and do not respond to leptin treatment, suggesting the presence of leptin tolerance and questioning the role of leptin as regulator of energy balance in humans. We thus performed detailed novel measurements and analyses of samples and data from our clinical trials biobank to investigate leptin effects on mechanisms of weight regulation in lean normo- and mildly hypo-leptinemic individuals without genetic disorders. We demonstrate that short-term leptin administration alters food intake during refeeding after fasting, whereas long-term leptin treatment reduces fat mass and body weight, and transiently alters circulating free fatty acids in lean mildly hypoleptinemic individuals. Leptin levels before treatment initiation and leptin dose do not predict the observed weight loss in lean individuals suggesting a saturable effect of leptin. In contrast to data from animal studies, leptin treatment does not affect energy expenditure, lipid utilization, SNS activity, heart rate, blood pressure or lean body mass.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Gorduras/metabolismo , Leptina/administração & dosagem , Obesidade/tratamento farmacológico , Magreza/tratamento farmacológico , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Adulto , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Energia , Feminino , Humanos , Masculino , Obesidade/metabolismo , Obesidade/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Magreza/metabolismo , Magreza/fisiopatologia , Adulto Jovem
2.
Aquat Toxicol ; 228: 105631, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32992089

RESUMO

Microplastics (MPs) are contaminants of emerging concern in the Arctic, but knowledge of their potential effects on Arctic plankton food webs remains scarce. We experimentally investigated ingestion and effects of MPs (20 µm polyethylene spheres) on the arctic copepods Calanus finmarchicus, C. glacialis and C. hyperboreus. These species dominate arctic zooplankton biomass and are relevant target species to investigate the potential impacts of MPs on the Arctic marine ecosystem. Females of each species were exposed to two concentrations of MPs (200 and 20,000 MPs L-1) in combination with different food (diatom) concentrations, reflecting high (3000-5000 cells mL-1, spring phytoplankton bloom) and low (50-500 cells mL-1, pre/post bloom) food conditions. MPs did not affect negatively fecal pellet production rates in any of the species at the studied exposure concentrations. However, egg production rates of copepods exposed to MPs were 8 times higher compared with the controls, which suggests that MP exposure can cause stress-induced spawning in arctic copepods. Microscopic examination of the fecal pellets confirmed ingested MPs in the three species (up to aprox. 1000 MPs cop-1 d-1). The number of MPs per pellet decreased exponentially with increasing food concentration. The daily ingestion of MPs per copepod was higher at low- food concentrations (250-500 cells mL-1). At our exposure conditions, the presence of MPs inside C. hyperboreus fecal pellets did not affect their sinking rates. Overall, our experimental research show that 1) acute exposure to virgin polyethylene MPs has a low impact on arctic Calanus species at environmentally relevant MP concentrations, independent of food availability, and 2) arctic copepods influence the environmental fate of plankton-sized MPs by exporting buoyant MPs from the surface layer to the sea floor via fecal pellets.


Assuntos
Copépodes/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Microplásticos/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Regiões Árticas , Ecossistema , Fezes/química , Feminino , Óvulo/efeitos dos fármacos , Óvulo/crescimento & desenvolvimento
3.
Proc Natl Acad Sci U S A ; 117(34): 20874-20880, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32764144

RESUMO

Maintaining energy homeostasis requires coordinating physiology and behavior both on an acute timescale to adapt to rapid fluctuations in caloric intake and on a chronic timescale to regulate body composition. Hypothalamic agouti-related peptide (AgRP)-expressing neurons are acutely activated by caloric need, and this acute activation promotes increased food intake and decreased energy expenditure. On a longer timescale, AgRP neurons exhibit chronic hyperactivity under conditions of obesity and high dietary fat consumption, likely due to leptin resistance; however, the behavioral and metabolic effects of chronic AgRP neuronal hyperactivity remain unexplored. Here, we use chemogenetics to manipulate Gq signaling in AgRP neurons in mice to explore the hypothesis that chronic activation of AgRP neurons promotes obesity. Inducing chronic Gq signaling in AgRP neurons initially increased food intake and caused dramatic weight gain, in agreement with published data; however, food intake returned to baseline levels within 1 wk, and body weight returned to baseline levels within 60 d. Additionally, we found that, when mice had elevated body weight due to chronic Gq signaling in AgRP neurons, energy expenditure was not altered but adiposity and lipid metabolism were both increased, even under caloric restriction. These findings reveal that the metabolic and behavioral effects of chronic Gq signaling in AgRP neurons are distinct from the previously reported effects of acute Gq signaling and also of leptin insensitivity.


Assuntos
Proteína Relacionada com Agouti/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Obesidade/metabolismo , Adiposidade/efeitos dos fármacos , Animais , Peso Corporal , Restrição Calórica , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Energia , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Feminino , Homeostase/efeitos dos fármacos , Hipotálamo/metabolismo , Leptina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Obesidade/fisiopatologia , Transdução de Sinais , Ganho de Peso/efeitos dos fármacos
4.
Toxicol Lett ; 332: 192-201, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32693020

RESUMO

Fenvalerate, a synthetic pyrethroid insecticide, is an environmental endocrine disruptor and neurodevelopmental toxicant. An early report found that pubertal exposure to high-dose fenvalerate impaired cognitive and behavioral development. Here, we aimed to further investigate the effect of pubertal exposure to low-dose fenvalerate on cognitive and behavioral development. Mice were orally administered with fenvalerate (0.2, 1.0 and 5.0 mg/kg) daily from postnatal day (PND) 28 to PND56. Learning and memory were assessed by Morris water maze. Anxiety-related activities were detected by open-field and elevated plus-maze. Increased anxiety activities were observed only in females exposed to fenvalerate. Spatial learning and memory were damaged only in females exposed to fenvalerate. Histopathology observed numerous scattered shrinking neurons and nuclear pyknosis in hippocampal CA1 region. Neuronal density was reduced in hippocampal CA1 region of fenvalerate-exposed mice. Mechanistically, hippocampal thyroid hormone receptor (TR)ß1 was down-regulated in a dose-dependent manner in females. In addition, TRα1 was declined only in females exposed to 5.0 mg/kg fenvalerate. Taken together, these suggests that pubertal exposure to low-dose fenvalerate impairs cognitive and behavioral development in a gender-dependent manner. Hippocampal TR signaling may be, at least partially, involved in fenvalerate-induced impairment of cognitive and behavioral development.


Assuntos
Transtornos Cognitivos/induzido quimicamente , Hipocampo/metabolismo , Inseticidas/toxicidade , Nitrilos/toxicidade , Piretrinas/toxicidade , Transdução de Sinais/efeitos dos fármacos , Hormônios Tireóideos , Animais , Ansiedade/induzido quimicamente , Ansiedade/psicologia , Peso Corporal/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Transtornos Cognitivos/psicologia , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Disruptores Endócrinos , Feminino , Hipocampo/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Neurônios/patologia , Receptores dos Hormônios Tireóideos/efeitos dos fármacos , Caracteres Sexuais
5.
Anim Sci J ; 91(1): e13409, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32524726

RESUMO

This study was aimed to explore the comparative acidifying properties of 2-hydroxy-4-(methylthio) butanoic acid (HMTBA) and a combination of DL-methionine (DLM) and acidifier in male broiler production. A total of 480 1-day-old broiler chicks were randomly divided into four treatments: A (low HMTBA, 0.057% HMTBA); B (low acidifier, 0.05% DLM + 0.057% acidifier); C (high HMTBA, 0.284% HMTBA); and D (high acidifier, 0.25% DLM + 0.284% acidifier). At 21 d, growth performance, chyme pH, digestive enzyme activities, and intestinal microflora were measured. The pH of crop, gizzard, and ileum contents was higher in the HMTBA treatment group than in DLM + acidifier treatment group. Furthermore, acidifier supplementation promoted growth of butyrate-producing bacteria such as Faecalibacterium, whereas high HMTBA (0.284%) inhibited the proliferation of acid-producing bacteria including Roseburia and Collinsella. The chymotrypsin activity was lower in the HMTBA group than in the DLM + acidifier group. In contrast, high-level HMTBA group showed higher average daily gain and average daily feed intake than the DLM + acidifier group. These results suggested that HMTBA work through different pathways with DLM plus acidifier.


Assuntos
Fenômenos Fisiológicos da Nutrição Animal/efeitos dos fármacos , Galinhas/crescimento & desenvolvimento , Galinhas/microbiologia , Galinhas/fisiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Metionina/análogos & derivados , Metionina/farmacologia , Animais , Quimotripsina/metabolismo , Papo das Aves , Ingestão de Alimentos/efeitos dos fármacos , Conteúdo Gastrointestinal , Moela das Aves , Concentração de Íons de Hidrogênio , Íleo , Masculino , Ganho de Peso/efeitos dos fármacos
6.
J Anim Sci ; 98(6)2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32379891

RESUMO

Porcine reproductive and respiratory syndrome virus (PRRSV) is an economically important disease, and the ingestion of soy isoflavones (ISF) may benefit PRRSV-infected pigs due to demonstrated anti-inflammatory and antiviral properties. The objective of this study was to quantify the effects of ISF consumption on fecal microbiome characteristics at different timepoints across a disease challenge and determine whether any changes, if present, elude to potential biological mechanisms for previously observed performance benefits. In total, 96 weaned barrows were group-housed in a Biosafety Level-2 containment facility and allotted to one of three experimental treatments that were maintained throughout the study: noninfected pigs receiving an ISF-devoid control diet (NEG, n = 24) and infected pigs receiving either the control diet (POS, n = 36) or that supplemented with total ISF in excess of 1,600 mg/kg (ISF, n = 36). Following a 7-d adaptation, pigs were inoculated intranasally with either a sham-control (phosphate-buffered saline) or live PRRSV (1 × 105 median tissue culture infectious dose[TCID]50/mL, strain NADC20). Fecal samples were collected from 48 individual pigs at pre-infection (-2 d post-inoculation [DPI]), peak-infection (10 DPI), and post-infection (144 DPI) timepoints. Extracted DNA was used to quantify fecal microbiota profiles via 16S bacterial rRNA sequencing. Differences in bacterial communities among diet groups were evaluated with principal coordinate analysis and permutational multivariate analysis of variance using UniFrac distance matrices based on both unweighted and weighted UniFrac distances using QIIME 2. All other data were analyzed by one-way ANOVA performed on square root transformations using R. Across all timepoints, only a few differences were observed due to ISF alone mainly in lowly abundant genera. The most notable differences observed were decreased relative abundance of Actinobacteria at 144 DPI between noninfected and infected treatments (P < 0.05), which is consistent with various dysbioses observed in other disease models. Our findings indicate that the differences present were mainly due to PRRSV-infection alone and not strongly influenced by diet, which implies that previously observed performance benefits conferred by dietary ISF are not likely due to the changes in microbiome composition.


Assuntos
Isoflavonas/farmacologia , Microbiota/efeitos dos fármacos , Síndrome Respiratória e Reprodutiva Suína/virologia , Vírus da Síndrome Respiratória e Reprodutiva Suína , Soja/química , Doenças dos Suínos/virologia , Ração Animal/análise , Animais , Dieta , Suplementos Nutricionais/análise , Ingestão de Alimentos/efeitos dos fármacos , Fezes/microbiologia , Masculino , Síndrome Respiratória e Reprodutiva Suína/microbiologia , Suínos , Doenças dos Suínos/microbiologia
7.
Lancet Diabetes Endocrinol ; 8(6): 524-534, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32445739

RESUMO

Insulin acts on the CNS to modulate behaviour and systemic metabolism. Disturbances in brain insulin action represent a possible link between metabolic and cognitive health. Current findings from human research suggest that boosting central insulin action in the brain modulates peripheral metabolism, enhancing whole-body insulin sensitivity and suppressing endogenous glucose production. Moreover, central insulin action curbs food intake by reducing the salience of highly palatable food cues and increasing cognitive control. Animal models show that the mesocorticolimbic circuitry is finely tuned in response to insulin, driven mainly by the dopamine system. These mechanisms are impaired in people with obesity, which might increase their risk of developing type 2 diabetes and associated diseases. Overall, current findings highlight the role of insulin action in the brain and its consequences on peripheral metabolism and cognition. Hence, improving central insulin action could represent a therapeutic option for people at an increased risk of developing metabolic and cognitive diseases.


Assuntos
Encéfalo/metabolismo , Ingestão de Alimentos/fisiologia , Metabolismo Energético/fisiologia , Insulina/sangue , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Sistema Nervoso Central/diagnóstico por imagem , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/sangue , Insulina/administração & dosagem , Resistência à Insulina/fisiologia
8.
Artigo em Inglês | MEDLINE | ID: mdl-32292065

RESUMO

In rats, overnight fasting reduces the ability of systemic cholecystokinin-8 (CCK) to suppress food intake and to activate cFos in the caudal nucleus of the solitary tract (cNTS), specifically within glucagon-like peptide-1 (GLP-1) and noradrenergic (NA) neurons of the A2 cell group. Systemic CCK increases vagal sensory signaling to the cNTS, an effect that is amplified by leptin and reduced by ghrelin. Since fasting reduces plasma leptin and increases plasma ghrelin levels, we hypothesized that peripheral leptin administration and/or antagonism of ghrelin receptors in fasted rats would rescue the ability of CCK to activate GLP-1 neurons and a caudal subset of A2 neurons that coexpress prolactin-releasing peptide (PrRP). To test this, cFos expression was examined in ad libitum-fed and overnight food-deprived (DEP) rats after intraperitoneal CCK, after coadministration of leptin and CCK, or after intraperitoneal injection of a ghrelin receptor antagonist (GRA) before CCK. In fed rats, CCK activated cFos in ~60% of GLP-1 and PrRP neurons. Few or no GLP-1 or PrRP neurons expressed cFos in DEP rats treated with CCK alone, CCK combined with leptin, or GRA alone. However, GRA pretreatment increased the ability of CCK to activate GLP-1 and PrRP neurons and also enhanced the hypophagic effect of CCK in DEP rats. Considered together, these new findings suggest that reduced behavioral sensitivity to CCK in fasted rats is at least partially due to ghrelin-mediated suppression of hindbrain GLP-1 and PrRP neural responsiveness to CCK.


Assuntos
Regulação do Apetite/efeitos dos fármacos , Colecistocinina/administração & dosagem , Ingestão de Alimentos/efeitos dos fármacos , Jejum/metabolismo , Comportamento Alimentar/efeitos dos fármacos , Grelina/sangue , Neurônios/efeitos dos fármacos , Rombencéfalo/efeitos dos fármacos , Animais , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Leptina/sangue , Masculino , Neurônios/metabolismo , Hormônio Liberador de Prolactina/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Sprague-Dawley , Receptores de Grelina/metabolismo , Rombencéfalo/metabolismo , Transdução de Sinais
9.
Am J Physiol Endocrinol Metab ; 318(5): E806-E816, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32228323

RESUMO

Previous studies indicate that inhibition of food intake by leptin is mediated by an integrated response to activation of hypothalamic and hindbrain receptors. This study tested whether loss of hindbrain leptin receptor signaling changed sensitivity to forebrain leptin. Injections of leptin-conjugated saporin (Lep-Sap) into the medial nucleus of the solitary tract (NTS) were used to destroy hindbrain leptin receptor-expressing neurons of male Sprague-Dawley rats. Controls were injected with saporin conjugated with a nonsense peptide (Blk-Sap). Lep-Sap had no effect on daily food intake or body weight, but expression of phosphorylated signal transducer and activator of transcription 3 (pSTAT3) in the NTS following a peripheral injection of leptin was abolished 26 days after Lep-Sap injections. To test forebrain leptin sensitivity, Lep-Sap and Blk-Sap rats received third-ventricle injections of 0, 0.05, 0.1, 0.25, or 0.5 µg leptin. Food intake was inhibited by 0.25 and 0.5 µg leptin in Blk-Sap rats, but there was no significant effect of leptin on food intake of Lep-Sap rats. There was no difference in hypothalamic pSTAT3 in unstimulated conditions, but pSTAT3 was lower in the dorsomedial region of the ventromedial nucleus of the hypothalamus (VMH) of Lep-Sap rats compared with Blk-Sap rats following a third-ventricle injection of 0.25 µg leptin. These results are consistent with previous data showing that loss of VMH leptin receptor-expressing cells prevents weight loss caused by fourth-ventricle leptin infusion and show that the integrated response between the hindbrain and forebrain is heavily dependent on leptin activity in the VMH.


Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Leptina/farmacologia , Neurônios/metabolismo , Prosencéfalo/efeitos dos fármacos , Receptores para Leptina/metabolismo , Rombencéfalo/metabolismo , Núcleo Hipotalâmico Ventromedial/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Masculino , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores para Leptina/genética
10.
J Pharmacol Exp Ther ; 374(1): 74-83, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32317372

RESUMO

Amylin treatment improves body weight and glucose control, although it is limited by a short action and need for high doses. Dual amylin and calcitonin receptor agonists (DACRAs) are dual amylin and calcitonin receptor agonists with beneficial effects beyond those of amylin. However, to what extent the additional benefits reside in their higher potency or their targeting of the calcitonin receptor remains unclear. Here we deconstruct the receptors involved in the effects of a DACRA, KBP-088, by comparing it to rat amylin (rAMY), rat calcitonin (rCT), and their combination in obese high-fat diet (HFD) and diabetic Zucker diabetic fatty (ZDF) rats. HFD-fed Sprague-Dawley rats and ZDF rats were treated for 4 weeks with KBP-088 (5 µg/kg per day), rAMY (300 µg/kg per day), rCT (300 µg/kg per day), and the combination of rAMY and rCT (300+300 µg/kg per day) using infusion pumps. Body weight, food intake, fasting glycemia, glycated hemoglobin type A1c levels, and glucose tolerance were assessed. In obese HFD-fed rats, KBP-088, rAMY, and the combination of rAMY and rCT significantly reduced body weight and improved glucose tolerance, whereas rCT alone had no effect. In diabetic ZDF rats, rCT was efficient in lowering fasting glycemia similar to rAMY, whereas dual activation by KBP-088 and the combination of rAMY and rCT were superior to activating either receptor alone. In conclusion, calcitonin therapy regulates fasting blood glucose in a diabetic rat model, thereby underscoring the importance of calcitonin receptor activation as well as the known role of amylin receptor agonism in the potent metabolic benefits of this group of peptides. SIGNIFICANCE STATEMENT: We deconstruct the receptors activated by dual amylin and calcitonin receptor agonist (DACRA) therapy to elucidate through which receptor the beneficial metabolic effects of the DACRAs are mediated. We show that calcitonin receptor activation is important for blood glucose regulation in diabetes. This is in addition to the known metabolic beneficial role of amylin receptor activation. These data help in understanding the potent metabolic benefits of the DACRAs and underline the potential of DACRAs as treatment for diabetes and obesity.


Assuntos
Glucose/metabolismo , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Receptores da Calcitonina/agonistas , Animais , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Ingestão de Alimentos/efeitos dos fármacos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Ratos
11.
Artigo em Inglês | MEDLINE | ID: mdl-32160019

RESUMO

The fatty acid, lauric acid (C12), and the amino acid, leucine (Leu) stimulate gut hormones, including CCK, associated with suppression of energy intake. In our recent study, intraduodenal infusion of a combination of C12 and l-tryptophan, at loads that individually did not affect energy intake, reduced energy intake substantially, associated with much greater stimulation of CCK. We have now investigated whether combined administration of C12 and Leu would enhance the intake-suppressant effects of each nutrient, when given at loads that each suppress energy intake individually. Sixteen healthy, lean males (age: 23 ± 2 yr) received, in randomized, double-blind fashion, 90-min intraduodenal infusions of control (saline), C12 (0.4 kcal/min), Leu (0.45 kcal/min), or C12+Leu (0.85 kcal/min). Antropyloroduodenal pressures were measured continuously and plasma CCK at 15-min intervals, and energy intake from a standardized buffet-meal, consumed immediately postinfusion, was quantified. All nutrient infusions stimulated plasma CCK compared with control (P < 0.05). Moreover, C12 and C12+Leu stimulated CCK compared with Leu (P < 0.05) (mean concentration, pmol/L; control: 2.3 ± 0.3, C12: 3.8 ± 0.3, Leu: 2.7 ± 0.3, and C12+Leu: 4.0 ± 0.4). C12+Leu, but not C12 or Leu, stimulated pyloric pressures (P < 0.05). C12+Leu and C12 reduced energy intake (P < 0.05), and there was a trend for Leu to reduce (P = 0.06) energy intake compared with control, with no differences between the three nutrient treatments (kcal; control: 1398 ± 84, C12: 1226 ± 80, Leu: 1260 ± 92, and C12+Leu: 1208 ± 83). In conclusion, combination of C12 and Leu, at the loads given, did not reduce energy intake beyond their individual effects, possibly because maximal effects had been evoked.


Assuntos
Colecistocinina/sangue , Ingestão de Energia , Motilidade Gastrointestinal/efeitos dos fármacos , Ácidos Láuricos/farmacologia , Leucina/farmacologia , Adolescente , Adulto , Apetite/efeitos dos fármacos , Método Duplo-Cego , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Ácidos Láuricos/administração & dosagem , Leucina/administração & dosagem , Masculino , Adulto Jovem
12.
Artigo em Inglês | MEDLINE | ID: mdl-32208925

RESUMO

Phoenixin is a 20-amino acid peptide (PNX-20) cleaved from the small integral membrane protein 20 (SMIM20), with multiple biological roles in mammals. However, its role in nonmammalian vertebrates is poorly understood. This research aimed to determine whether PNX-20 influences feeding and metabolism in zebrafish. The mRNAs encoding SMIM20 and its putative receptor, super conserved receptor expressed in brain 3 (SREB3), are present in both central and peripheral tissues of zebrafish. Immunohistochemical analysis confirmed the presence of PNX-like immunoreactivity in the gut and in zebrafish liver (ZFL) cell line. We also found that short-term fasting (7 days) significantly decreased smim20 mRNA expression in the brain, gut, liver, gonads, and muscle, which suggests a role for PNX-20 in food intake regulation. Indeed, single intraperitoneal injection of 1,000 ng/g body wt PNX-20 reduced feeding in both male and female zebrafish, likely in part by enhancing hypothalamic cart and reducing hypothalamic/gut preproghrelin mRNAs. Furthermore, the present results demonstrated that PNX-20 modulates the expression of genes involved in glucose transport and metabolism in ZFL cells. In general terms, such PNX-induced modulation of gene expression was characterized by the upregulation of glycolytic genes and the downregulation of gluconeogenic genes. A kinetic study of the ATP production rate from both glycolytic and mitochondrial pathways demonstrated that PNX-20-treated ZFL cells exhibited significantly higher ATP production rate associated with glycolysis than control cells. This confirms a positive role for PNX-20 on glycolysis. Together, these results indicate that PNX-20 is an anorexigen with important metabolic roles in zebrafish.


Assuntos
Depressores do Apetite/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Glucose/metabolismo , Glicólise/efeitos dos fármacos , Proteínas de Homeodomínio/farmacologia , Fragmentos de Peptídeos/farmacologia , Proteínas de Peixe-Zebra/farmacologia , Peixe-Zebra/metabolismo , Animais , Regulação do Apetite/efeitos dos fármacos , Linhagem Celular , Feminino , Regulação da Expressão Gênica , Glicólise/genética , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Masculino , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Transdução de Sinais , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
13.
J Nutr ; 150(5): 1126-1134, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32125421

RESUMO

BACKGROUND: Stevia is a zero-calorie alternative to caloric sugars. Substituting caloric sweeteners with noncaloric sweeteners reduces available energy, but their effects on appetite, subsequent food intake, and neurocognitive responses are still unclear. OBJECTIVE: The aim was to examine whether sweetness with or without calories influences food intake, appetite, blood glucose concentrations, and attentional bias (AB) to food cues. METHODS: This was a randomized, controlled, double-blind crossover study. Healthy participants [n = 20; aged 27 ± 5 y,  55% female; BMI (kg/m2): 21.8 ± 1.5] completed 5 visits, consuming 5 study beverages: 330 mL water (control, no sweet taste, no calories) and either 330 mL water containing 40 g glucose or sucrose (sweet taste; calories, both 160 kcal), maltodextrin (no sweet taste; calories, 160 kcal), or 240 ppm stevia (sweet taste, no calories). Glucose and stevia beverages were matched for sweetness. Subjective appetite ratings and blood glucose were measured at baseline and at 15, 30, and 60 min postprandially. At 15 min participants performed a visual-dot probe task to assess AB to food cues; at 30 min, participants were offered an ad libitum lunch; food intake was measured. RESULTS: Subjective appetite ratings showed that preload sweetness and calorie content both affected appetite. The total AUC for glycemia was significantly higher after the caloric beverages (mean ± SD: maltodextrin, 441 ± 57.6;  glucose, 462 ± 68.1;  sucrose, 425 ± 53.6 mmol × min × L-1 ) compared with both stevia (320 ± 34.2 mmol × min × L-1) and water (304 ± 32.0 mmol × min × L-1) (all P < 0.001). Total energy intake (beverage and meal) was significantly lower after the stevia beverage (727 ± 239 kcal) compared with water (832 ± 198 kcal,  P = 0.013), with no significant difference between the water and caloric beverages (P = 1.00 for water vs. maltodextrin, glucose, and sucrose). However, food-related AB did not differ across conditions (P = 0.140). CONCLUSIONS: This study found a beneficial and specific effect of a stevia beverage consumed prior to a meal on appetite and energy intake in healthy adults. This trial is registered at clinicaltrials.gov as NCT03711084.


Assuntos
Apetite/efeitos dos fármacos , Bebidas , Glicemia/análise , Ingestão de Energia/efeitos dos fármacos , Glicosídeos/administração & dosagem , Stevia/química , Adulto , Estudos Cross-Over , Método Duplo-Cego , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Glucose/administração & dosagem , Humanos , Almoço , Masculino , Polissacarídeos/administração & dosagem , Saciação/efeitos dos fármacos , Sacarose/administração & dosagem , Paladar
14.
Metabolism ; 105: 154171, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32006557

RESUMO

BACKGROUND: Based on the metabolic effect of exogenous ATPase inhibitory factor 1 (IF1) on glucose metabolism, we tested whether IF1 treatment is effective in ameliorating weight gain and whether its effects are sex specific. METHODS: HFD-fed C57BL/6 mice were treated with IF1 (5 mg/kg body weight, injected intraperitoneally). The underlying mechanisms of effect of IF1 on body weight were investigated in vitro and in vivo. Associations between genotypes of IF1 and obesity and relevant phenotype were further tested at the population level. RESULTS: Chronic treatment with IF1 significantly decreased body weight gain by regulating food intake of HFD-fed male mice. IF1 activated the AKT/mTORC pathway and modulated the expression of appetite genes in the hypothalamus of HFD-fed male mice and its effect was confirmed in hypothalamic cell lines as well as hypothalamic primary cells. This required the interaction of IF1 with ß-F1-ATPase on the plasma membrane of hypothalamic cells, which led to an increase in extracellular ATP production. In addition, IF1 treatment showed sympathetic nerve activation as measured by serum norepinephrine levels and UCP-1 expression in the subcutaneous fat of HFD-fed male mice. Notably, administration of recombinant IF1 to HFD-fed ovariectomized female mice showed remarkable reductions in food intake as well as body weight, which was not observed in wild-type 5-week female mice. Lastly, sex-specific genotype associations of IF1 with obesity prevalence and metabolic traits were demonstrated at the population level in humans. IF1 genetic variant (rs3767303) was significantly associated with lower prevalence of obesity and lower levels of body mass index, waist circumference, hemoglobin A1c, and glucose response area only in male participants. CONCLUSION: IF1 is involved in weight regulation by controlling food intake and potentially sympathetic nerve activation in a sex-specific manner.


Assuntos
Peso Corporal/efeitos dos fármacos , Obesidade/genética , Proteínas/genética , Proteínas/farmacologia , Animais , Apetite/genética , Dieta Hiperlipídica , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Variação Genética , Genótipo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Pessoa de Meia-Idade , Obesidade/epidemiologia , Ovariectomia , Prevalência , Caracteres Sexuais , Ganho de Peso/efeitos dos fármacos
16.
J Dairy Sci ; 103(3): 2217-2232, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31928758

RESUMO

Our objective was to evaluate effects of feeding milk replacer (MR) at 2 feeding rates on digestion, intake, and growth of young dairy calves, via a meta-analytical approach using individual data. A database was developed from 10 published studies from the Nurture Research Center (Provimi; Brookville, OH), in which 26 dietary treatments and 491 calves from 0 to 8 wk of age in 13 nursery trials, and 22 dietary treatments and 485 calves from 8 to 16 wk of age in 13 grower trials occurred. Male Holstein calves (n = 491; initial body weight 42.8 ± 4.9 kg) were randomly assigned to 1 of 2 treatments: (1) moderate (MOD), 0.64 to 0.66 kg of dry matter (DM)/d for the first 35 to 39 d, followed by half the allotment per d for 3 to 7 d, fed at the a.m. feeding only; (2) high (HI), 0.92 to 1.07 kg of DM/d for the first 35 to 44 d, followed by half the allotment per d for 5 to 7 d, fed at the a.m. feeding only. Calves were weaned at 6 to 7 wk of age. Milk replacer ranged from 24.8 to 28.6% crude protein (CP) and 17.6 to 20.2% fat; starter ranged from 17.3 to 22.2% CP and 3.0 to 4.3% fat on a DM basis. On d 56 calves (n = 485) moved into pens (4 calves/pen) by treatments and were fed starter (19.4 to 22.3% CP and 3.4 to 4.6% fat, DM basis) blended with 5% hay until d 112. In all nursery trials (d 0 to 56), calves fed MOD had lower average daily gain (ADG; 0.634 vs. 0.545 kg/d), gain/DMI (0.488 vs. 0.466 kg/kg), and hip width change (0.069 vs. 0.064 cm/d), but greater starter intake (0.473 vs. 0.696 kg/d) compared with calves fed HI. Apparent total-tract digestibility of DM (73.3 vs. 78.4%), organic matter (OM; 74.1 vs. 79.0%), CP (74.8 vs. 78.9%), and neutral detergent fiber (NDF; 40.8 vs. 53.9%) were greater for calves fed MOD vs. HI when estimated during wk 8. In all grower trials (d 56 to 112), ADG (1.015 vs. 0.976 kg/d), gain/DMI (0.375 vs. 0.349 kg/kg), and hip width change (0.089 vs. 0.081 cm/d) were greater, but dry feed intake per kg of BW0.75 did not differ (87.8 vs. 88.2 g/d) for calves previously fed MOD vs. HI. Apparent digestibility of DM (78.7 vs. 76.0%), OM (79.8 vs. 77.0%), CP (80.5 vs. 78.4%), and NDF (54.8 vs. 45.8%) were greater for calves fed MOD vs. HI when estimated between wk 11 to 13. Over the entire 112-d period, calves fed MOD had lower ADG (0.805 vs. 0.784 kg/d) but tended to have greater hip width change (8.415 vs. 8.589 cm) compared with calves fed HI. Under the conditions of this study, feeding higher MR rates caused calves to partially lose growth advantage during the weaning transition and further decreased BW gain and structural growth in the grower period (d 56 to 112), which could be due to reductions in nutrient digestibility as a result of feeding more MR.


Assuntos
Bovinos/fisiologia , Ingestão de Alimentos/efeitos dos fármacos , Substitutos do Leite/administração & dosagem , Ração Animal/análise , Animais , Peso Corporal/efeitos dos fármacos , Bovinos/crescimento & desenvolvimento , Dieta/veterinária , Fibras na Dieta/metabolismo , Digestão/efeitos dos fármacos , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/fisiologia , Masculino , Desmame
17.
Psychopharmacology (Berl) ; 237(4): 957-966, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31897573

RESUMO

RATIONALE AND OBJECTIVES: Although clozapine is effective in treating schizophrenia, it is associated with adverse side effects including weight gain and metabolic syndrome. Despite this, the role of clozapine on feeding behaviour and food intake has not been thoroughly characterised. Clozapine has a broad pharmacological profile, with affinities for several neurotransmitter receptors, including serotonin (5-hydroxytriptamine, 5-HT) and histamine. Given that the serotonin 5-HT2C receptor and histaminergic H1 receptor are involved in aspects of feeding behaviour, the effect of clozapine on feeding may be linked to its action at these receptors. METHODS: We assessed, in rats, the effect of acute and subchronic administration of clozapine on responding for food under a progressive ratio (PR) schedule under conditions of food restriction and satiety. We also examined the effect of antagonists of the serotonin 5-HT2C and histaminergic H1 receptors on the same schedule. Clozapine reliably increased responding for food, even when rats had ad libitum access to food. The effect of clozapine on responding for food was reproduced by combined (but not individual) antagonism of the serotonin 5-HT2C and histaminergic H1 receptors. CONCLUSION: These findings show that clozapine enhances the motivation to work for food, that this effect is stable over repeated testing, and is independent of hunger state of the animal. This effect may relate to a combined action of clozapine at the serotonin 5-HT2C and histaminergic H1 receptors.


Assuntos
Antipsicóticos/farmacologia , Clozapina/farmacologia , Comportamento Alimentar/fisiologia , Motivação/fisiologia , Receptor 5-HT2C de Serotonina/fisiologia , Receptores 5-HT1 de Serotonina/fisiologia , Animais , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Ingestão de Alimentos/psicologia , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/psicologia , Masculino , Motivação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Esquema de Reforço , Antagonistas da Serotonina/farmacologia , Ganho de Peso/efeitos dos fármacos , Ganho de Peso/fisiologia
18.
Psychopharmacology (Berl) ; 237(4): 1091-1106, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31897576

RESUMO

Eating disorders are frequently triggered by stress and are more prevalent in women than men. First signs often appear during early adolescence, but the biological basis for the sex-specific differences is unknown. Central administration of native relaxin-3 (RLN3) peptide or chimeric/truncated analogues produces differential effects on food intake and HPA axis activity in adult male and female rats, but the precise role of endogenous RLN3 signalling in metabolic and neuroendocrine control is unclear. Therefore, we examined the effects of microRNA-induced depletion (knock-down) of RLN3 mRNA/(peptide) production in neurons of the brainstem nucleus incertus (NI) in female rats on a range of physiological, behavioural and neurochemical indices, including food intake, body weight, anxiety, plasma corticosterone, mRNA levels of key neuropeptides in the paraventricular nucleus of hypothalamus (PVN) and limbic neural activity patterns (reflected by c-fos mRNA). Validated depletion of RLN3 in NI neurons of female rats (n = 8) produced a small, sustained (~ 2%) decrease in body weight, an imbalance in food intake and an increase in anxiety-like behaviour in the large open field, but not in the elevated plus-maze or light/dark box. Furthermore, NI RLN3 depletion disrupted corticosterone regulation, increased oxytocin and arginine-vasopressin, but not corticotropin-releasing factor, mRNA, in PVN, and decreased basal levels of c-fos mRNA in parvocellular and magnocellular PVN, bed nucleus of stria terminalis and the lateral hypothalamic area, brain regions involved in stress and feeding. These findings support a role for NI RLN3 neurons in fine-tuning stress and neuroendocrine responses and food intake regulation in female rats.


Assuntos
Ansiedade/metabolismo , Peso Corporal/fisiologia , Ingestão de Alimentos/fisiologia , Sistema Límbico/metabolismo , Proteínas do Tecido Nervoso/deficiência , Núcleos da Rafe/metabolismo , Relaxina/deficiência , Animais , Ansiedade/psicologia , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/psicologia , Feminino , Técnicas de Silenciamento de Genes/métodos , Sistema Límbico/efeitos dos fármacos , MicroRNAs/administração & dosagem , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Núcleos da Rafe/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Relaxina/antagonistas & inibidores , Relaxina/genética
19.
Am J Physiol Endocrinol Metab ; 318(3): E343-E356, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31891537

RESUMO

Diabetic nephropathy (DN) is one of the most important renal complications associated with diabetes, and the mechanisms are yet to be fully understood. To date, few studies have shown the antioxidant effects of 1α,25-dihydroxyvitamin-D3 [1,25(OH)2D3] on hyperglycemia-induced renal injury. The aim of the present study was to explore the potential mechanism by which 1,25(OH)2D3 reduced oxidative stress in diabetic rat kidneys. In this study, we established a vitamin D-deficient spontaneous diabetes model: 5-6 wk of age Zucker diabetic fatty (ZDF) rats were treated with or without 1,25(OH)2D3 for 7 wk, age-matched Zucker lean rats served as control. Results showed that ZDF rats treated with 1,25(OH)2D3 had decreased body mass, food intake, water intake, and urine volume. 1,25(OH)2D3 ameliorated urine glucose, blood glucose and abnormal glucose tolerance. Additionally, 1,25(OH)2D3 significantly lowered microalbuminuria, decreased the glomerular basement membrane thickness, and in some degree inhibited glomerular hypertrophy, mesangial expansion, and tubular dilatation. Furthermore, 1,25(OH)2D3 attenuated renal oxidative damage, as reflected by the levels of malondialdehyde, reduced glutathione, 4-hydroxynonenal, 8-hydroxy-2'-deoxyguanosine, and reactive oxygen species production, and notably inhibited poly(ADP-ribose) polymerase-1 (PARP1), activated sirtuin 1 (SIRT1), and decreased the expression of NADPH oxidase 4 (NOX4). Of interest, the abovementioned proteins could be involved in the antioxidant mechanism of 1,25(OH)2D3 in diabetic rat kidneys. Our study showed that oxidative stress might be a major contributor to DN pathogenesis and uncovered the antioxidant role of 1,25(OH)2D3 in diabetic nephropathy that was associated with the PARP1/SIRT1/ NOX4 pathway.


Assuntos
Calcitriol/farmacologia , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/prevenção & controle , NADPH Oxidase 4/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Poli(ADP-Ribose) Polimerase-1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental/genética , Ingestão de Líquidos/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Glucose/metabolismo , Teste de Tolerância a Glucose , Masculino , Ratos , Ratos Zucker , Urodinâmica/efeitos dos fármacos
20.
Am J Physiol Endocrinol Metab ; 318(4): E514-E524, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31990576

RESUMO

We examined the methionine aminopeptidase 2 inhibitor fumagillin in dogs consuming a high-fat and -fructose diet (HFFD). In pilot studies (3 dogs that had consumed HFFD for 3 yr), 8 wk of daily treatment with fumagillin reduced food intake 29%, weight 6%, and the glycemic excursion during an oral glucose tolerance test (OGTT) 44%. A second group of dogs consumed the HFFD for 17 wk: pretreatment (weeks 0-4), treatment with fumagillin (FUM; n = 6), or no drug (Control, n = 8) (weeks 4-12), washout period (weeks 12-16), and fumagillin or no drug for 1 wk (week 17). OGTTs were performed at 0, 4, 11, and 16 wk. A hyperinsulinemic hyperglycemic clamp was performed in week 12; 4 chow-fed dogs underwent identical clamps. Kilocalories per day intake during the treatment period was 2,067 ± 50 (Control) versus 1,824 ± 202 (FUM). Body weights (kg) increased 1.9 ± 0.3 vs. 2.7 ± 0.8 (0-4 wk) and 1.2 ± 0.2 vs. -0.02 ± 0.9 (4-12 wk) in Control versus fumagillin. The OGTT glycemic response was 30% greater in Control versus fumagillin at 11 wk. Net hepatic glucose uptake (NHGU; mg·kg-1·min-1) in the Chow, Control, and fumagillin dogs was ~1.5 ± 0.6, -0.1 ± 0.1, and 0.3 ± 0.4 (with no portal glucose infusion) and 3.1 ± 0.6, 0.5 ± 0.3, and 1.5 ± 0.5 (portal glucose infusion at 4 mg·kg-1·min-1), respectively. Fumagillin improved glucose tolerance and NHGU in HFFD dogs, suggesting methionine aminopeptidase 2 (MetAP2) inhibitors have the potential for improving glycemic control in prediabetes and diabetes.


Assuntos
Aminopeptidases/antagonistas & inibidores , Cicloexanos/farmacologia , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos Insaturados/farmacologia , Frutose/efeitos adversos , Glucose/metabolismo , Glucose/farmacologia , Metaloendopeptidases/antagonistas & inibidores , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Dieta , Cães , Ingestão de Alimentos/efeitos dos fármacos , Técnica Clamp de Glucose , Teste de Tolerância a Glucose , Resistência à Insulina , Masculino , Sesquiterpenos/farmacologia
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