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1.
Life Sci ; 258: 118204, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32763296

RESUMO

AIMS: Liver kinase B1 (LKB1) is a serine/threonine kinase. Although many biological functions of LKB1 have been identified, the role of hypothalamic LKB1 in the regulation of central energy metabolism and susceptibility to obesity is unknown. Therefore, we constructed POMC neuron-specific LKB1 knockout mice (PomcLkb1 KO) and studied it at the physiological, morphological, and molecular biology levels. MAIN METHODS: Eight-week-old male PomcLkb1 KO mice and their littermates were fed a standard chow fat diet (CFD) or a high-fat diet (HFD) for 3 months. Body weight and food intake were monitored. Dual-energy X-ray absorptiometry was used to measure the fat mass and lean mass. Glucose and insulin tolerance tests and serum biochemical markers were evaluated in the experimental mice. In addition, the levels of peripheral lipogenesis genes and central energy metabolism were measured. KEY FINDINGS: PomcLkb1 KO mice did not exhibit impairments under normal physiological conditions. After HFD intervention, the metabolic phenotype of the PomcLkb1 KO mice changed, manifesting as increased food intake and an enhanced obesity phenotype. More seriously, PomcLkb1 KO mice showed increased leptin resistance, worsened hypothalamic inflammation and reduced POMC neuronal expression. SIGNIFICANCE: We provide evidence that LKB1 in POMC neurons plays a significant role in regulating energy homeostasis. LKB1 in POMC neurons emerges as a target for therapeutic intervention against HFD-induced obesity and metabolic diseases.


Assuntos
Deleção de Genes , Neurônios/enzimologia , Obesidade/enzimologia , Pró-Opiomelanocortina/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Tecido Adiposo/patologia , Animais , Dieta Hiperlipídica , Epididimo/patologia , Comportamento Alimentar , Regulação da Expressão Gênica , Glucose/metabolismo , Hipotálamo/patologia , Inflamação/patologia , Leptina/metabolismo , Fígado/enzimologia , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Obesidade/sangue , Obesidade/patologia , Pró-Opiomelanocortina/genética , Ganho de Peso
2.
Int J Obes (Lond) ; 44(9): 1810-1817, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32647360

RESUMO

Overweight and obesity are major risk factors for diabetes, cardiovascular disease, and lung disease. These diseases are the most commonly reported health conditions that predispose individuals with SARS-CoV-2 infection to require hospitalization including intensive care unit admissions. The innate immune response is the host's first line of defense against a human coronavirus infection. However, most coronaviruses are armed with one strategy or another to overcome host antiviral defense, and the pathogenicity of the virus is related to its capacity to suppress host immunity. The multifaceted nature of obesity including its effects on immunity can fundamentally alter the pathogenesis of acute respiratory distress syndrome and pneumonia, which are the major causes of death due to SARS-CoV-2 infection. Elevated circulating leptin concentrations are a hallmark of obesity, which is associated with a leptin-resistant state. Leptin is secreted by adipocytes in proportion to body fat and regulates appetite and metabolism through signaling in the hypothalamus. However, leptin also signals through the Jak/STAT and Akt pathways, among others, to modulate T cell number and function. Thus, leptin connects metabolism with the immune response. Therefore, it seems appropriate that its dysregulation would have serious consequences during an infection. We propose that leptin may be the link between obesity and its high prevalence as a comorbidity of the SARS-CoV-2 infection. In this article, we present a synthesis of the mechanisms underpinning susceptibility to respiratory viral infections and the contribution of the immunomodulatory effects of obesity to the outcome.


Assuntos
Infecções por Coronavirus , Leptina , Obesidade , Pandemias , Pneumonia Viral , Betacoronavirus , Comorbidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Humanos , Leptina/sangue , Leptina/imunologia , Leptina/metabolismo , Obesidade/epidemiologia , Obesidade/imunologia , Obesidade/metabolismo , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/metabolismo , Transdução de Sinais/imunologia
3.
Gene ; 758: 144957, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-32683081

RESUMO

Leptin receptor (LEPR) gene play a pivotal role in the regulation of fat deposition and energy homeostasis. This study investigated the presence and frequency of polymorphisms of bovine LEPR gene and determine whether the polymorphisms are associated with the fat deposition in two Chinese beef cattle breeds. Quantitative real-time polymerase chain reactions identified that the expression of LEPR gene was highest in the liver and subcutaneous fat. Four single nucleotide polymorphisms (SNPs) were identified including g.24169C > T, g.24256T > A, g.24267 G > C and g.24413T > A. A greater backfat thickness was associated with the AA genotype of g.24256T > A compared to the TT genotype. A greater intramuscular fat content was associated with the GG genotype of g.24267 G > C compared to the CC genotype. Both g.24169C > T and g.24413T > A were not correlated with fat deposition. These results indicated that the SNP g.24256T > A and g.24267 G > C of LEPR gene may be useful markers for genetic improvement of fat deposition in Chinese beef cattle breeds.


Assuntos
Adiposidade/genética , Distribuição da Gordura Corporal , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Animais , Bovinos , Frequência do Gene/genética , Estudos de Associação Genética , Genótipo , Leptina/metabolismo , Polimorfismo de Nucleotídeo Único/genética
4.
Life Sci ; 257: 118036, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32622949

RESUMO

AIMS: Anti-obesity effects and improved leptin sensitivity from n-3 polyunsaturated fatty acids (n-3 PUFAs) have been reported in diet-induced obese animals. This study sought to determine the beneficial central effects and mechanism of docosahexaenoic acid (DHA, 22:6 n-3) in high-fat (HF) diet fed mice. MAIN METHODS: Male C57BL/6J mice were given HF diet with or without intracerebroventricular (icv) injection of docosahexaenoic acid (DHA, 22:6 n-3) for two days. Central leptin sensitivity, hypothalamic inflammation, leptin signaling molecules and tyrosine hydroxylase (TH) were examined by central leptin sensitivity test and Western blot. Furthermore, the expression of hepatic genes involved in lipid metabolism was examined by RT-PCR. KEY FINDINGS: We found that icv administration of DHA not only reduced energy intake and body weight gain but also corrected the HF diet-induced hypothalamic inflammation. DHA decreased leptin signaling inhibitor SOCS3 and improved the leptin JAK2-Akt signaling pathways in the hypothalamus. Furthermore, icv administration of DHA improved the effects of leptin in the regulation of mRNA expression of enzymes related to lipogenesis, fatty acid ß-oxidation, and cholesterol synthesis in the liver. DHA increased leptin-induced activation of TH in the hypothalamus. SIGNIFICANCE: Therefore, increasing central DHA concentration may prevent the deficit of hypothalamic regulation, which is associated with disorders of energy homeostasis in the liver as a result of a high-fat diet.


Assuntos
Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Leptina/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Ingestão de Energia/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Inflamação/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Transdução de Sinais/efeitos dos fármacos
5.
Adv Exp Med Biol ; 1259: 89-112, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32578173

RESUMO

Leptin is a hormone that plays a major role as mediator of long-term regulation of energy balance, suppressing food intake, and stimulating weight loss. More recently, important physiological roles other than controlling appetite and energy expenditure have been suggested for leptin, including neuroendocrine, reparative, reproductive, and immune functions. These emerging peripheral roles let hypothesize that leptin can modulate also cancer progression. Indeed, many studies have demonstrated that elevated chronic serum concentrations of leptin, frequently seen in obese subjects, represent a stimulatory signal for tumor growth. Current knowledge indicates that also different non-tumoral cells resident in tumor microenvironment may respond to leptin creating a favorable soil for cancer cells. In addition, leptin is produced also within the tumor microenvironment creating the possibility for paracrine and autocrine action. In this review, we describe the main mechanisms that regulate peripheral leptin availability and how leptin can shape tumor microenvironment.


Assuntos
Leptina/metabolismo , Neoplasias/metabolismo , Microambiente Tumoral , Animais , Metabolismo Energético , Humanos , Neoplasias/patologia , Obesidade/metabolismo
6.
Isr Med Assoc J ; 22(6): 374-377, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32558444

RESUMO

BACKGROUND: The effect of weight reduction following bariatric surgery is already well known. OBJECTIVES: To investigate the effects of abdominoplasty on metabolic markers indicative of weight loss. METHODS: The authors prospectively enrolled consecutive obese patients after laparoscopic sleeve gastrectomy. They were candidates for post-bariatric surgery abdominoplasty. The authors measured metabolic markers one day prior to surgery, 24 hours after, and 3 months following surgery. They recorded medical and demographic parameters. RESULTS: Sixteen patients were recruited for participation in the study. Mean age was 47 years and 88% of the patients were female. Bariatric surgery achieved a mean decline in body mass index of 13.8 kg/m2. All patients underwent abdominoplasty. Leptin and insulin levels were slightly increased at 3 months postoperative. No significant changes were observed in glucose, hemoglobin, or triglycerides throughout the study. CONCLUSIONS: In a cohort of obese patients undergoing laparoscopic sleeve gastrectomy followed by abdominoplasty, no significant changes were noted in a patient's metabolic profiles. The results suggest that abdominoplasty has no effect on the metabolic markers tested in contrast to other reports; however, the cosmetic, behavioral, and psychological advantages of abdominoplasty are well established.


Assuntos
Abdominoplastia , Cirurgia Bariátrica , Gastrectomia , Insulina/metabolismo , Leptina/metabolismo , Obesidade/cirurgia , Perda de Peso , Adulto , Cirurgia Bariátrica/métodos , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
7.
Life Sci ; 257: 117994, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32569780

RESUMO

Sleep-disordered breathing is characterized by disruptions of normal breathing patterns during sleep. Obesity is closely related to hypoventilation or apnea and becomes a primary risk factor for sleep-disordered breathing. Leptin, a peptide secreted by adipose tissue, has been implicated in central control of breathing. Activation of the retrotrapezoid nucleus (RTN) neurons, a critical central respiratory chemoreceptor candidate, potentiates a central drive to breathing. Here, we ask whether the disordered leptin signaling in the RTN is responsible for obesity-related hypoventilation. In a diet induced obesity (DIO) mouse model, the hypercapnic ventilatory response (HCVR) was assessed and the cellular leptin signaling in the RTN was examined. Our main findings demonstrate that DIO mice exhibit overweight, hypercapnia, high levels of serum and cerebrospinal leptin. During exposure to room air, DIO mice manifest basal hypoventilation with a rapid and shallow breathing pattern. Exposure to CO2 elicits the impaired HCVR in DIO mice. In addition, both the number of CO2-activated neurons and expression of TASK-2 channels in the RTN are dramatically reduced in DIO mice. Moreover, there is leptin signaling disorder in RTN neurons in DIO mice, including a significant decrease in leptin-activated RTN neurons, downregulation of phosphorylated STAT3 and upregulation of SOCS3. Altogether, we suggest that the disordered leptin/STAT3/SOCS3 signaling pathway in the RTN plays a role in obesity-related hypoventilation.


Assuntos
Células Quimiorreceptoras/metabolismo , Leptina/metabolismo , Obesidade/metabolismo , Animais , Dióxido de Carbono/metabolismo , Células Quimiorreceptoras/fisiologia , Hipercapnia/metabolismo , Leptina/fisiologia , Masculino , Bulbo/metabolismo , Bulbo/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Obesidade/fisiopatologia , Respiração , Mecânica Respiratória/fisiologia , Transdução de Sinais , Sono/fisiologia
8.
Clin Sci (Lond) ; 134(12): 1537-1553, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32556103

RESUMO

Hyperuricaemia (HUA) significantly increases the risk of metabolic syndrome and is strongly associated with the increased prevalence of high serum free fatty acids (FFAs) and insulin resistance. However, the underlying mechanisms are not well established, especially the effect of uric acid (UA) on adipose tissue, a vital organ in regulating whole-body energy and FFA homeostasis. In the present study, we noticed that adipocytes from the white adipose tissue of patients with HUA were hypertrophied and had decreased UCP1 expression. To test the effects of UA on adipose tissue, we built both in vitro and in vivo HUA models and elucidated that a high level of UA could induce hypertrophy of adipocytes, inhibit their hyperplasia and reduce their beige-like characteristics. According to mRNA-sequencing analysis, UA significantly decreased the expression of leptin in adipocytes, which was closely related to fatty acid metabolism and the AMPK signalling pathway, as indicated by KEGG pathway analysis. Moreover, lowering UA using benzbromarone (a uricosuric agent) or metformin-induced activation of AMPK expression significantly attenuated UA-induced FFA metabolism impairment and adipose beiging suppression, which subsequently alleviated serum FFA elevation and insulin resistance in HUA mice. Taken together, these observations confirm that UA is involved in the aetiology of metabolic abnormalities in adipose tissue by regulating leptin-AMPK pathway, and metformin could lessen HUA-induced serum FFA elevation and insulin resistance by improving adipose tissue function via AMPK activation. Therefore, metformin could represent a novel treatment strategy for HUA-related metabolic disorders.


Assuntos
Adipócitos/patologia , Tecido Adiposo Bege/patologia , Tecido Adiposo Branco/patologia , Ácidos Graxos não Esterificados/sangue , Hiperuricemia/sangue , Hiperuricemia/tratamento farmacológico , Resistência à Insulina , Metformina/uso terapêutico , Células 3T3-L1 , Adenilato Quinase/metabolismo , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo Bege/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Adulto , Animais , Ativação Enzimática , Feminino , Humanos , Hipertrofia , Leptina/metabolismo , Lipogênese , Lipólise , Masculino , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Transdução de Sinais , Triglicerídeos/metabolismo , Ácido Úrico/sangue
9.
Life Sci ; 254: 117764, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32407841

RESUMO

AIMS: Emerging evidence suggests that during gestation the in utero environment programs metabolism and can increase risk of obesity in adult offspring. Our aim was to study how alterations in maternal diets during gestation might alter body weight evolution, circulating leptin levels and caloric intake in offspring, leading to changes in body composition. MATERIALS AND METHODS: We fed gestating rats either a control diet (CD), high fat diet (HFD) or an isocaloric low protein diet (LPD), and examined the repercussions in offspring fed similar diets post-weaning on birth weight, body weight evolution, body composition, insulin sensitivity, glucose tolerance and in the relationship between plasma leptin concentration and caloric intake in offspring during growth and development. KEY FINDS: Offspring from dams fed LPD maintained reduced body weight with greater % lean mass and consumed fewer calories despite having leptin levels similar to controls. On the other hand, offspring from dams fed a HFD were insulin resistant and maintained increased body weight and % fat mass, while consuming more calories than controls despite elevated leptin concentrations. Therefore the uterine environment, modulated primarily through maternal nutrition, modified the relationship between circulating leptin levels, body fat, and caloric intake in the offspring, and dams fed a HFD produced offspring with excess adiposity, insulin resistance, and leptin resistance into adulthood. SIGNIFICANCE: Our data indicates that in utero environmental factors affected by maternal diet program alterations in the set point around which leptin regulates body weight in offspring into adulthood contributing to obesity.


Assuntos
Fenômenos Fisiológicos da Nutrição Materna/fisiologia , Obesidade/etiologia , Fenômenos Fisiológicos da Nutrição Pré-Natal/fisiologia , Tecido Adiposo/metabolismo , Adiposidade/fisiologia , Animais , Animais Recém-Nascidos , Peso ao Nascer , Composição Corporal , Peso Corporal , Dieta Hiperlipídica , Gorduras na Dieta , Ingestão de Energia , Feminino , Resistência à Insulina , Lactação , Leptina/metabolismo , Masculino , Obesidade/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ratos , Ratos Sprague-Dawley , Desmame
10.
PLoS One ; 15(5): e0227527, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32374776

RESUMO

Type 2 diabetes and obesity are associated with back pain in juveniles and adults and are implicated in intervertebral disc (IVD) degeneration. Hypercaloric Western diets are associated with both obesity and type 2 diabetes. The objective of this study was to determine if obesity and type 2 diabetes result in spinal pathology in a sex-specific manner using in vivo diabetic and dietary mouse models. Leptin is an appetite-regulating hormone, and its deficiency leads to polyphagia, resulting in obesity and diabetes. Leptin is also associated with IVD degeneration, and increased expression of its receptor was identified in degenerated IVDs. We used young, leptin receptor deficient (Db/Db) mice to mimic the effect of diet and diabetes on adolescents. Db/Db and Control mice were fed either Western or Control diets, and were sacrificed at 3 months of age. Db/Db mice were obese, while only female mice developed diabetes. Female Db/Db mice displayed altered IVD morphology, with increased intradiscal notochordal band area, suggesting delayed IVD cell proliferation and differentiation, rather than IVD degeneration. Motion segments from Db/Db mice exhibited increased failure risk with decreased torsional failure strength. Db/Db mice also had inferior bone quality, which was most prominent in females. We conclude that obesity and diabetes due to impaired leptin signaling contribute to pathological changes in vertebrae, as well as an immature IVD phenotype, particularly of females, suggesting a sex-dependent role of leptin in the spine.


Assuntos
Diabetes Mellitus Tipo 2/genética , Degeneração do Disco Intervertebral/genética , Leptina/genética , Obesidade/genética , Receptores para Leptina/genética , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Dieta Ocidental/efeitos adversos , Modelos Animais de Doenças , Feminino , Humanos , Disco Intervertebral/metabolismo , Disco Intervertebral/patologia , Degeneração do Disco Intervertebral/metabolismo , Degeneração do Disco Intervertebral/patologia , Leptina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NOD , Obesidade/metabolismo , Obesidade/patologia , Receptores para Leptina/deficiência , Caracteres Sexuais , Transdução de Sinais/genética , Coluna Vertebral/metabolismo , Coluna Vertebral/patologia
11.
Nat Commun ; 11(1): 1914, 2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32313051

RESUMO

Obesity is associated with the activation of cellular responses, such as endoplasmic reticulum (ER) stress. Here, we show that leptin-deficient ob/ob mice display elevated hypothalamic ER stress as early as postnatal day 10, i.e., prior to the development of obesity in this mouse model. Neonatal treatment of ob/ob mice with the ER stress-relieving drug tauroursodeoxycholic acid (TUDCA) causes long-term amelioration of body weight, food intake, glucose homeostasis, and pro-opiomelanocortin (POMC) projections. Cells exposed to ER stress often activate autophagy. Accordingly, we report that in vitro induction of ER stress and neonatal leptin deficiency in vivo activate hypothalamic autophagy-related genes. Furthermore, genetic deletion of autophagy in pro-opiomelanocortin neurons of ob/ob mice worsens their glucose homeostasis, adiposity, hyperphagia, and POMC neuronal projections, all of which are ameliorated with neonatal TUDCA treatment. Together, our data highlight the importance of early life ER stress-autophagy pathway in influencing hypothalamic circuits and metabolic regulation.


Assuntos
Autofagia/fisiologia , Estresse do Retículo Endoplasmático/fisiologia , Metabolismo Energético/fisiologia , Hipotálamo/metabolismo , Leptina/metabolismo , Neurogênese/fisiologia , Adiposidade , Animais , Antivirais/farmacologia , Autofagia/efeitos dos fármacos , Autofagia/genética , Proteína 7 Relacionada à Autofagia/genética , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Colagogos e Coleréticos/farmacologia , Modelos Animais de Doenças , Ingestão de Alimentos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/genética , Comportamento Alimentar , Homeostase , Hiperfagia/metabolismo , Leptina/genética , Masculino , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Neuroendocrinologia , Neurogênese/efeitos dos fármacos , Obesidade/metabolismo , Pró-Opiomelanocortina/metabolismo , Ácido Tauroquenodesoxicólico
12.
Sheng Li Xue Bao ; 72(2): 175-180, 2020 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-32328611

RESUMO

The present study was aimed to clarify the signaling molecular mechanism by which fibroblast growth factor 21 (FGF21) regulates leptin gene expression in adipocytes. Differentiated 3T3-F442A adipocytes were used as study object. The mRNA expression level of leptin was detected by fluorescence quantitative RT-PCR. The phosphorylation levels of proteins of signal transduction pathways were detected by Western blot. The results showed that FGF21 significantly down-regulated the mRNA expression level of leptin in adipocytes, and FGF21 receptor inhibitor BGJ-398 could completely block this effect. FGF21 up-regulated the phosphorylation levels of ERK1/2 and AMPK in adipocytes. Either ERK1/2 inhibitor SCH772984 or AMPK inhibitor Compound C could partially block the inhibitory effect of FGF21, and the combined application of these two inhibitors completely blocked the effect of FGF21. Neither PI3K inhibitor LY294002 nor Akt inhibitor AZD5363 affected the inhibitory effect of FGF21 on leptin gene expression. These results suggest that FGF21 may inhibit leptin gene expression by activating ERK1/2 and AMPK signaling pathways in adipocytes.


Assuntos
Adipócitos/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Leptina/metabolismo , Células 3T3 , Adenilato Quinase , Animais , Regulação para Baixo , Sistema de Sinalização das MAP Quinases , Camundongos , Fosforilação , Transdução de Sinais
13.
J Dairy Sci ; 103(5): 4765-4776, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32229118

RESUMO

Dairy cows consume inadequate amounts of feed in early lactation and during conditions and diseases such as excessive fatness, heat stress, and infectious diseases. Affected cows often experience increases in plasma concentrations of acute phase proteins consistent with the negative effect of inflammation on appetite. The acute phase protein orosomucoid 1 (ORM1), also known as alpha-1-acid glycoprotein, was recently reported to reduce appetite in the mouse through its ability to bind the full-length leptin receptor (Ob-Rb) and activate appetite-suppressing signal transducer and activator of transcription 3 (STAT3) signaling. These observations raise the possibility that ORM1 exerts appetite-suppressing effects in dairy cattle during periods of increased inflammatory tone. The applicability of this model was assessed in 2 ways. First, we asked whether ORM1 is regulated during periods of inadequate appetite such as the transition from late pregnancy to early lactation and periods of increased inflammatory tone. Plasma ORM1 was invariant in late pregnancy but increased 2.5-fold between parturition and d 7 of lactation. Gene expression studies showed that liver was the major source of this elevation with little contribution by adipose tissue or mammary gland. Additional studies showed that plasma ORM1 was not increased further by excessive fatness or by reproductive dysfunction in early lactation and was completely unresponsive to inflammatory stimuli such as heat stress or intravascular administration of the endotoxin lipopolysaccharide during established lactation. Second, we tested the ability of ORM1 to trigger STAT3 signaling through Ob-Rb using Chinese hamster ovary K1 (CHO-K1) cells transfected with a STAT3 expression plasmid. In this configuration, CHO-K1 cells did not express Ob-Rb and were incapable of leptin-induced STAT3 phosphorylation. Leptin responsiveness was conferred by co-transfecting with bovine Ob-Rb, with leptin causing increases of 5.7-fold in STAT3 phosphorylation and 2.1-fold in the expression of the STAT3-dependent gene, SOCS3. In contrast, neither bovine or human ORM1 triggered STAT3 phosphorylation irrespective of dose and period of incubation tested. In summary, bovine ORM1 is not increased during periods of increased inflammatory tone except in early lactation and is incapable of Ob-Rb-dependent STAT3 signaling. Overall, these data are inconsistent with ORM1 mediating the appetite-suppressing effects of inflammation in cattle through Ob-Rb.


Assuntos
Regulação do Apetite/fisiologia , Bovinos/metabolismo , Lactação/fisiologia , Orosomucoide/metabolismo , Receptores para Leptina/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Proteínas da Fase Aguda/metabolismo , Tecido Adiposo/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Feminino , Leptina/metabolismo , Gravidez , Regulação para Cima
14.
Nat Commun ; 11(1): 1517, 2020 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-32251290

RESUMO

Leptin stimulates the sympathetic nervous system (SNS), energy expenditure, and weight loss; however, the underlying molecular mechanism remains elusive. Here, we uncover Sh2b1 in leptin receptor (LepR) neurons as a critical component of a SNS/brown adipose tissue (BAT)/thermogenesis axis. LepR neuron-specific deletion of Sh2b1 abrogates leptin-stimulated sympathetic nerve activation and impairs BAT thermogenic programs, leading to reduced core body temperature and cold intolerance. The adipose SNS degenerates progressively in mutant mice after 8 weeks of age. Adult-onset ablation of Sh2b1 in the mediobasal hypothalamus also impairs the SNS/BAT/thermogenesis axis; conversely, hypothalamic overexpression of human SH2B1 has the opposite effects. Mice with either LepR neuron-specific or adult-onset, hypothalamus-specific ablation of Sh2b1 develop obesity, insulin resistance, and liver steatosis. In contrast, hypothalamic overexpression of SH2B1 protects against high fat diet-induced obesity and metabolic syndromes. Our results unravel an unrecognized LepR neuron Sh2b1/SNS/BAT/thermogenesis axis that combats obesity and metabolic disease.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Fígado Gorduroso/patologia , Resistência à Insulina , Neurônios/metabolismo , Obesidade/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Tecido Adiposo Marrom/inervação , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/patologia , Animais , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Fígado Gorduroso/etiologia , Feminino , Técnicas de Introdução de Genes , Técnicas de Inativação de Genes , Humanos , Hipotálamo/patologia , Leptina/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Transgênicos , Obesidade/etiologia , Receptores para Leptina/metabolismo , Sistema Nervoso Simpático/fisiologia , Termogênese/fisiologia
15.
Poult Sci ; 99(3): 1409-1420, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32115028

RESUMO

Lysine is the second most limiting amino acid after methionine and is considered the most limiting amino acid for growth in poultry. Lysine requirement for broiler chickens has changed over the years. Leptin and adiponectin represent 2 adipokines that mediate metabolism by eliciting satiety effects whereas ghrelin peptide hormone influences appetite. We hypothesize that this affects growth performance of chicks. This study evaluates the effect of varying dietary lysine homeostasis on performance of broiler chickens through satiety- and appetite-mediating hormones. In 3 replications, 270 one-day-old chicks were reared for 8 wk feeding on diets comprising 0.85, 1.14, and 1.42% lysine during the starter period and 0.75, 1.00, and 1.25% lysine during the grower period. These concentrations of lysine represent 75% (low lysine), 100% (control), and 125% (high lysine) of National Research Council recommendation for broiler chickens. Feed and water were provided for ad libitum consumption. At 8 wk of age, liver, pancreas, brain, and hypothalamus tissues were collected from 18 birds randomly selected from each treatment, snap frozen in liquid nitrogen, and stored at -80°C until use. Total RNA was extracted, and cDNA was synthesized for quantitative real-time PCR assays. Low lysine concentration caused slow growth and high mortality. There was significant upregulation of ghrelin in the hypothalamus and pancreas, and leptin and adiponectin in the hypothalamus and liver, and downregulation of ghrelin in the intestines. At low lysine concentrations, adiponectin was not expressed in both pancreas and intestines. High lysine concentration exhibited increased growth, upregulation of ghrelin in the liver, and downregulation of ghrelin in the intestines, and both adiponectin and leptin in the liver. The expression of ghrelin was negatively correlated with the expression of adiponectin and leptin (P < 0.05) in the liver, hypothalamus, and pancreas. Expression of leptin was positively correlated with adiponectin in the hypothalamus and liver (P < 0.05), exhibiting satiety effects when the concentrations of lysine were low.


Assuntos
Apetite/genética , Galinhas/fisiologia , Lisina/metabolismo , Neuropeptídeos/genética , Hormônios Peptídicos/genética , Saciação , Adiponectina/genética , Adiponectina/metabolismo , Ração Animal/análise , Animais , Galinhas/genética , Galinhas/crescimento & desenvolvimento , Dieta/veterinária , Suplementos Nutricionais/análise , Relação Dose-Resposta a Droga , Regulação para Baixo , Perfilação da Expressão Gênica/veterinária , Grelina/genética , Grelina/metabolismo , Homeostase , Leptina/genética , Leptina/metabolismo , Lisina/administração & dosagem , Neuropeptídeos/metabolismo , Hormônios Peptídicos/metabolismo , Distribuição Aleatória , Regulação para Cima
17.
Am J Clin Nutr ; 111(4): 804-813, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32069352

RESUMO

BACKGROUND: Early-life exposure to improved nutrition is associated with decreased risk of diabetes but increased risk of obesity. Leptin positively correlates with adiposity and has glucose-lowering effects, thus it may mediate the association of early-life nutrition and long-term glycemic status. OBJECTIVES: We aimed to investigate the role of leptin in the differential association between early-life nutrition and the risks of obesity and diabetes. METHODS: We analyzed data from a Guatemalan cohort who were randomly assigned at the village level to receive nutritional supplements as children. We conducted mediation analysis to examine the role of leptin in the associations of early-life nutrition and adult cardiometabolic outcomes. RESULTS: Among 1112 study participants aged (mean ± SD) 44.1 ± 4.2 y, 60.6% were women. Cardiometabolic conditions were common: 40.2% of women and 19.4% of men were obese, and 53.1% of women and 41.0% of men were hyperglycemic or diabetic. Median (IQR) leptin concentration was 15.2 ng/mL (10.2-17.3 ng/mL) in women and 2.7 ng/mL (1.3-5.3 ng/mL) in men. Leptin was positively correlated with BMI (Spearman's ρ was 0.6 in women, 0.7 in men). Women exposed to improved nutrition in early life had 2.8-ng/mL (95% CI: 0.3, 5.3 ng/mL) higher leptin and tended to have lower fasting glucose (-0.8 mmol/L; -1.8, 0.2 mmol/L, nonsignificant) than unexposed women. There were no significant differences in leptin (-0.7 ng/mL; -2.1, 0.8 ng/mL) or fasting glucose (0.2 mmol/L; -0.5, 0.9 mmol/L) in men exposed to improved nutrition in early life compared with unexposed men. Leptin mediated 34.9% of the pathway between early-life nutrition and fasting glucose in women. The mediation in women was driven by improved pancreatic ß-cell function. We did not observe the mediation effect in men. CONCLUSIONS: Leptin mediated the glucose-lowering effect of early-life nutrition in women but not in men.


Assuntos
Suplementos Nutricionais/análise , Leptina/metabolismo , Obesidade/dietoterapia , Adiposidade , Adulto , Glicemia/metabolismo , Índice de Massa Corporal , Estudos de Coortes , Feminino , Índice Glicêmico , Guatemala , Humanos , Insulina/metabolismo , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Obesidade/metabolismo , Obesidade/fisiopatologia , População Rural
18.
Clín. investig. arterioscler. (Ed. impr.) ; 32(1): 8-14, ene.-feb. 2020. graf, ilus
Artigo em Espanhol | IBECS | ID: ibc-187002

RESUMO

Introducción: El incremento de grasa miocárdica ha sido propuesto como uno de los principales precursores de la disfunción miocárdica de etiología diabética independiente de la enfermedad arterial coronaria. Sin embargo, actualmente se carece de biomarcadores que reflejen el contenido de grasa miocárdica para la detección clínica de esta patología. Métodos: Las correlaciones entre el contenido de triglicéridos cardíacos y los niveles plasmáticos de las principales moléculas alteradas durante la diabetes y los niveles cardíacos de ARNm de genes implicados en el metabolismo cardíaco (Cd36 y Pdk4) han sido exploradas en un modelo murino de resistencia a la insulina inducida por una dieta con alto contenido en grasas. Resultados: En ratones resistentes a la insulina, la dieta grasa aumentó los niveles de triglicéridos del miocardio, en comparación con animales controles alimentados con una dieta estándar. El contenido de triglicéridos cardíacos se encontró directamente asociado con los niveles plasmáticos de glucosa, triglicéridos, VLDL, resistina y leptina. Además, se observó una correlación inversa entre el contenido de triglicéridos y los niveles cardíacos de ARNm de Cd36 y Pdk4. Conclusiones: Nuestros datos revelan que el contenido cardíaco de triglicéridos se encuentra asociado con un perfil bioquímico plasmático alterado y con una reprogramación de la expresión de genes dirigida a atenuar el impacto de la acumulación ectópica de lípidos en miocardio


Introduction: The increase in myocardial fat has been proposed as one of the main precursors of myocardial dysfunction due to diabetic aetiology, independently of coronary artery disease. However, biomarkers reflecting the myocardial fat content for the clinical detection of this pathology are currently lacking. Methods: Correlations between 4cardiac triglyceride content and plasma levels of major altered molecules during diabetes and cardiac mRNA levels of genes involved in cardiac metabolism (Cd36 and Pdk4) have been explored in a murine model of insulin resistance induced by a high-fat diet. Results: In insulin-resistant mice, the fatty diet increased myocardial triglyceride levels, compared to control animals fed with a standard diet. The content of cardiac triglycerides was directly associated with plasma levels of glucose, triglycerides, VLDL, resistin and leptin. In addition, an inverse correlation was observed between the content of cardiac triglycerides and the cardiac mRNA levels of Cd36 and Pdk4. Conclusions: Our data reveal that the cardiac triglyceride content is associated with altered plasma biochemical profile and reprogramming of gene expression aimed to mitigate the impact of ectopic lipid accumulation in the myocardium


Assuntos
Animais , Camundongos , Masculino , Cardiomiopatias/veterinária , Resistência à Insulina , Gorduras na Dieta , Triglicerídeos/análise , Biomarcadores/sangue , Metabolismo dos Lipídeos , Ácidos Graxos/metabolismo , Cardiomiopatias/etiologia , Triglicerídeos/metabolismo , Glicemia/metabolismo , Lipoproteínas VLDL/metabolismo , Leptina/metabolismo , Resistina/metabolismo , Miocárdio/patologia , RNA/metabolismo , Ácidos Graxos/sangue
19.
J Anim Sci ; 98(3)2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32064516

RESUMO

Neutering is a risk factor for pet obesity, which reduces the quality and length of life. Dietary interventions may serve as preventive and therapeutic options for pet obesity. The objective of this study was to evaluate the effects of specially formulated diets on body weight (BW), body composition, and blood hormones and metabolites of adult female dogs after spay surgery. All procedures were approved by the University of Illinois Institutional Animal Care and Use Committee prior to experimentation. Twenty-eight healthy adult intact female Beagles (3.02 ± 0.7 yr; 10.28 ± 0.8 kg; body condition score [BCS]: 4.98 ± 0.57) were used in a longitudinal study. Twenty-four dogs were spayed and randomly allotted to one of three experimental diets: 1) moderate-protein, moderate-fiber diet (control; COSP), 2) high-protein, high-fiber diet (HP-HF), or 3) high-protein, high-fiber diet plus omega-3 and medium-chain fatty acids (HP-HF-O). Four dogs were sham-operated and fed the control diet (COSH). Food intake, BW, BCS, blood hormones and metabolites, body composition (via dual-energy X-ray absorptiometry scans), and voluntary physical activity (via Actical devices) were measured over time. After spay, dogs were fed to maintain BW for 12 wk (restricted phase), then allowed to overeat for 12 wk (ad libitum phase). Change from baseline data was analyzed for treatment, time, and treatment × time effects as well as treatment, feeding regimen, and treatment × feeding regimen effects. During the first 12 wk, HP-HF and HP-HF-O had lower (P < 0.01) blood cholesterol than COSH and COSP. During the second 12 wk, HP-HF and HP-HF-O ate more (P < 0.01) food (g/d) than COSH. BCS change for COSP was greater (P < 0.01) than COSH from week 21 to 24, but HP-HF and HP-HF-O were not different. When comparing data by feeding regimen, HP-HF and HP-HF-O had a greater reduction in serum cholesterol (P < 0.001) than COSH and COSP. During the second 12 wk, all spayed dogs consumed more (P < 0.01) food than COSH. However, COSH, HP-HF, and HP-HF-O had a lower (P < 0.001) increase in BCS than COSP. HP-HF-O and COSH had similar serum leptin during weeks 12 to 24. COSP had higher (P ≤ 0.01) serum C-reactive protein than HP-HF-O. Overall, body fat increase in COSP was greater (P < 0.05) than for COSH at week 24, while HP-HF and HP-HF-O were intermediate. Our results indicate that an HP-HF diet can limit weight gain and body fat increase and attenuate serum cholesterol, triglycerides, and leptin concentrations in dogs after spay surgery.


Assuntos
Composição Corporal , Dieta/veterinária , Doenças do Cão/prevenção & controle , Histerectomia/veterinária , Condicionamento Físico Animal , Tecido Adiposo/metabolismo , Animais , Fibras na Dieta/metabolismo , Cães , Feminino , Leptina/metabolismo , Estudos Longitudinais , Obesidade/metabolismo , Obesidade/prevenção & controle , Obesidade/veterinária
20.
Life Sci ; 247: 117446, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32081662

RESUMO

AIMS: Previous studies showed a close relationship between obesity and asthma. In this study, we investigated the expression of endoplasmic reticulum (ER) stress genes in the lung tissue of obese ovalbumin (OVA)-sensitized male and female rats. MAIN METHODS: The rats were divided into eight groups (n = 5 per group) as follows: female and male rats fed with normal diet (FND and MND, respectively), female and male OVA-sensitized rats fed with normal diet (F-OND and M-OND, respectively), female and male rats fed with high-fat diet (F-HFD and M-HFD, respectively), female and male OVA-sensitized rats fed with high-fat diet (F-OHFD and M-OHFD, respectively). All rats were fed with a high-fat diet or standard pelts for 8 weeks, and for another 4 weeks, they were sensitized by OVA or saline. At the end of the study, lung tissue NF-kB protein level was assessed, and ER stress markers genes expression was determined by Real Time-PCR. KEY FINDING: OVA-sensitization and diet-induced obesity caused the curve of methacholine concentration-response to shift to the left. In addition, the results indicated that the EC50 (the effective concentration of methacholine generating 50% of peak response) in F-OHFD rats was statistically lower than that of the M-OHFD group (p < 0.05). Moreover, the results showed that diet-induced obesity increased the expression of ATF4, ATF6, GRP78, XBP-1, and CHOP as well as the protein level of NF-kB in this experimental model of asthma, markedly in the F-OHFD group. SIGNIFICANCE: The results suggest that ER stress may be involved in the pathogenesis of asthma observed in obese OVA-sensitized rats, especially in the female animals.


Assuntos
Estresse do Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Leptina/metabolismo , NF-kappa B/metabolismo , Ovalbumina/metabolismo , Animais , Asma/metabolismo , Dieta Hiperlipídica , Retículo Endoplasmático/genética , Feminino , Regulação da Expressão Gênica , Proteínas de Choque Térmico HSP70/metabolismo , Pulmão , Masculino , Proteínas de Membrana/metabolismo , Cloreto de Metacolina/metabolismo , NF-kappa B/genética , Obesidade/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais , Fatores de Tempo
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