RESUMEN
Mammalian hibernators survive prolonged periods of cold and resource scarcity by temporarily modulating normal physiological functions, but the mechanisms underlying these adaptations are poorly understood. The hibernation cycle of thirteen-lined ground squirrels (Ictidomys tridecemlineatus) lasts for 5-7 months and comprises weeks of hypometabolic, hypothermic torpor interspersed with 24-48-h periods of an active-like interbout arousal (IBA) state. We show that ground squirrels, who endure the entire hibernation season without food, have negligible hunger during IBAs. These squirrels exhibit reversible inhibition of the hypothalamic feeding center, such that hypothalamic arcuate nucleus neurons exhibit reduced sensitivity to the orexigenic and anorexigenic effects of ghrelin and leptin, respectively. However, hypothalamic infusion of thyroid hormone during an IBA is sufficient to rescue hibernation anorexia. Our results reveal that thyroid hormone deficiency underlies hibernation anorexia and demonstrate the functional flexibility of the hypothalamic feeding center.
Asunto(s)
Anorexia , Ghrelina , Hibernación , Hipotálamo , Sciuridae , Animales , Hibernación/fisiología , Sciuridae/fisiología , Anorexia/fisiopatología , Anorexia/metabolismo , Hipotálamo/metabolismo , Ghrelina/metabolismo , Ghrelina/deficiencia , Leptina/deficiencia , Leptina/metabolismo , Núcleo Arqueado del Hipotálamo/metabolismo , Neuronas/metabolismo , Neuronas/fisiología , Masculino , Hormonas Tiroideas/metabolismo , Nivel de Alerta/fisiología , Femenino , Estaciones del Año , Conducta Alimentaria/fisiologíaRESUMEN
Lipodystrophy syndromes are rare diseases of genetic or acquired origin, characterized by quantitative and qualitative defects in adipose tissue. The metabolic consequences of lipodystrophy syndromes, such as insulin resistant diabetes, hypertriglyceridemia and hepatic steatosis, are frequently very difficult to treat, resulting in significant risks of acute and/or chronic complications and of decreased quality of life. The production of leptin by lipodystrophic adipose tissue is decreased, more severely in generalized forms of lipodystrophy, where adipose tissue is absent from almost all body fat depots, than in partial forms of the disease, where lipoatrophy affects only some parts of the body and can be associated with increased body fat in other anatomical regions. Several lines of evidence in preclinical and clinical models have shown that leptin replacement therapy could improve the metabolic complications of lipodystrophy syndromes. Metreleptin, a recombinant leptin analogue, was approved as an orphan drug to treat the metabolic complications of leptin deficiency in patients with generalized lipodystrophy in the USA or with either generalized or partial lipodystrophy in Japan and Europe. In this brief review, we will discuss the benefits and limitations of this therapy, and the new expectations arising from the recent development of a therapeutic monoclonal antibody able to activate the leptin receptor.
Asunto(s)
Terapia de Reemplazo de Hormonas , Leptina , Lipodistrofia , Leptina/uso terapéutico , Leptina/análogos & derivados , Leptina/deficiencia , Humanos , Lipodistrofia/tratamiento farmacológico , Terapia de Reemplazo de Hormonas/métodos , Tejido Adiposo/metabolismo , Tejido Adiposo/efectos de los fármacos , Síndrome , AnimalesRESUMEN
Obesity is a chronic disease caused by excessive fat accumulation that impacts the body and brain health. Insufficient leptin or leptin receptor (LepR) is involved in the disease pathogenesis. Leptin is involved with several neurological processes, and it has crucial developmental roles. We have previously demonstrated that leptin deficiency in early life leads to permanent developmental problems in young adult mice, including an imbalance in energy homeostasis, alterations in melanocortin and the reproductive system and a reduction in brain mass. Given that in humans, obesity has been associated with brain atrophy and cognitive impairment, it is important to determine the long-term consequences of early-life leptin deficiency on brain structure and memory function. Here, we demonstrate that leptin-deficient (LepOb) mice exhibit altered brain volume, decreased neurogenesis and memory impairment. Similar effects were observed in animals that do not express the LepR (LepRNull). Interestingly, restoring the expression of LepR in 10-week-old mice reverses brain atrophy, in addition to neurogenesis and memory impairments in older animals. Our findings indicate that leptin deficiency impairs brain development and memory, which are reversible by restoring leptin signalling in adulthood.
Asunto(s)
Encéfalo , Leptina , Neurogénesis , Receptores de Leptina , Animales , Receptores de Leptina/deficiencia , Receptores de Leptina/genética , Receptores de Leptina/metabolismo , Ratones , Encéfalo/metabolismo , Leptina/deficiencia , Leptina/metabolismo , Neurogénesis/fisiología , Ratones Noqueados , Ratones Endogámicos C57BL , Masculino , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/genética , Atrofia/patologíaRESUMEN
Leptin an adipokine with potent effects on energy balance and body weight plays an important role in defining bone architecture in growing mammals. However, major changes in body weight can also influence morphology of trabecular and cortical bone. Therefore, we examined the impact of leptin deficiency on tibia and vertebral body 3D bone architecture independent of changes in body weight. Furthermore, advances in computational 3D image analysis suggest that average morphological values may mask regional specific differences in trabecular bone thickness. The study utilized leptin-deficient Ob/Ob mice (n = 8) weight-paired to C57BL/6 (C57) control mice (n = 8) which were split into either lean or obese groups for 24 ± 2 weeks. Whole tibias and L3 vertebrae were fixed before high resolution microcomputed tomography (µCT) scanning was performed. Leptin deficiency independent of body weight reduced tibia cortical bone volume, trabecular bone volume/tissue volume, number, and mineral density. Mean tibia trabecular thickness showed no significant differences between all groups; however, significant changes in trabecular thickness were found when analyzed by region. This study demonstrates that leptin deficiency significantly impacts tibia and vertebral body trabecular and cortical bone 3D architecture independent of changes in body weight.
Asunto(s)
Leptina , Tibia , Animales , Masculino , Ratones , Peso Corporal , Densidad Ósea , Leptina/deficiencia , Ratones Endogámicos C57BL , Obesidad , Columna Vertebral/diagnóstico por imagen , Tibia/diagnóstico por imagen , Cuerpo Vertebral , Microtomografía por Rayos XRESUMEN
During obesity, tissue macrophages increase in number and become proinflammatory, thereby contributing to metabolic dysfunction. Lipoprotein lipase (LPL), which hydrolyzes triglyceride in lipoproteins, is secreted by macrophages. However, the role of macrophage-derived LPL in adipose tissue remodeling and lipoprotein metabolism is largely unknown. To clarify these issues, we crossed leptin-deficient Lepob/ob mice with mice lacking the Lpl gene in myeloid cells (Lplm-/m-) to generate Lplm-/m-;Lepob/ob mice. We found the weight of perigonadal white adipose tissue (WAT) was increased in Lplm-/m-;Lepob/ob mice compared with Lepob/ob mice due to substantial accumulation of both adipose tissue macrophages and collagen that surrounded necrotic adipocytes. In the fibrotic epidydimal WAT of Lplm-/m-;Lepob/ob mice, we observed an increase in collagen VI and high mobility group box 1, while α-smooth muscle cell actin, a marker of myofibroblasts, was almost undetectable, suggesting that the adipocytes were the major source of the collagens. Furthermore, the adipose tissue macrophages from Lplm-/m-;Lepob/ob mice showed increased expression of genes related to fibrosis and inflammation. In addition, we determined Lplm-/m-;Lepob/ob mice were more hypertriglyceridemic than Lepob/ob mice. Lplm-/m-;Lepob/ob mice also showed slower weight gain than Lepob/ob mice, which was primarily due to reduced food intake. In conclusion, we discovered that the loss of myeloid Lpl led to extensive fibrosis of perigonadal WAT and hypertriglyceridemia. In addition to illustrating an important role of macrophage LPL in regulation of circulating triglyceride levels, these data show that macrophage LPL protects against fibrosis in obese adipose tissues.
Asunto(s)
Tejido Adiposo Blanco , Colágeno Tipo IV , Hipertrigliceridemia , Lipoproteína Lipasa , Obesidad , Actinas/metabolismo , Tejido Adiposo Blanco/patología , Animales , Colágeno Tipo IV/metabolismo , Fibrosis , Hipertrigliceridemia/genética , Hipertrigliceridemia/patología , Leptina/deficiencia , Leptina/genética , Lipoproteína Lipasa/genética , Lipoproteínas/metabolismo , Ratones , Ratones Obesos , Obesidad/genética , Obesidad/metabolismo , Obesidad/patología , Triglicéridos/sangreRESUMEN
Therapeutic approach for NAFLD is limited and there are no approved drugs. Pioglitazone (PGZ), a thiazolidinedione (TZD) that acts via peroxisome proliferator activated receptor gamma (PPARγ) is the only agent that has shown consistent benefit and efficacy in clinical trials. However, the mechanism of its therapeutic effect on NAFLD remains unclear. The poor understanding may be due to problems with mouse, a species most used for animal experiments. TZDs exacerbate fatty liver in mouse models while they improve it in rat models like in human patients. Therefore, we compared the effects of TZDs including PGZ and rosiglitazone (RGZ) in ob/ob mice and Lepmkyo/Lepmkyo rats, models of leptin-deficient obesity, and A-ZIP/F-1 mice and seipin knockout (SKO) rats, models of generalized lipodystrophy. Pparg mRNA expression was markedly upregulated in fatty livers of mouse models while it was unchanged in rat models. TZDs exacerbated fatty liver in ob/ob and A-ZIP/F-1 mice, improved it in Lepmkyo/Lepmkyo rats and showed no effect in SKO rats. Gene expression analyses of Pparg and its target gene, Fsp27 revealed that PPARγ in the adipose tissue is the exclusive therapeutic target of TZDs in rats but PPARγ in the liver in addition to the adipose tissue is also a major site of actions for TZDs in mice. Although the response to TZDs in mice is the complete opposite of that in human patients, no report has pointed out the problem with TZD studies using mouse models so far. The present study might provide useful suggestions in research on TZDs.
Asunto(s)
Hígado Graso/tratamiento farmacológico , Metabolismo de los Lípidos/efectos de los fármacos , PPAR gamma/metabolismo , Pioglitazona/uso terapéutico , Tiazolidinedionas/uso terapéutico , Animales , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Hígado Graso/etiología , Hígado Graso/metabolismo , Leptina/deficiencia , Lipodistrofia/complicaciones , Masculino , Ratones Endogámicos C57BL , Obesidad/complicaciones , PPAR gamma/agonistas , Pioglitazona/farmacología , Ratas Transgénicas , Tiazolidinedionas/farmacologíaRESUMEN
Obesity has repeatedly been linked to reorganization of the gut microbiome, yet to this point obesity therapeutics have been targeted exclusively toward the human host. Here, we show that gut microbe-targeted inhibition of the trimethylamine N-oxide (TMAO) pathway protects mice against the metabolic disturbances associated with diet-induced obesity (DIO) or leptin deficiency (Lepob/ob). Small molecule inhibition of the gut microbial enzyme choline TMA-lyase (CutC) does not reduce food intake but is instead associated with alterations in the gut microbiome, improvement in glucose tolerance, and enhanced energy expenditure. We also show that gut microbial CutC inhibition is associated with reorganization of host circadian control of both phosphatidylcholine and energy metabolism. This study underscores the relationship between microbe and host metabolism and provides evidence that gut microbe-derived trimethylamine (TMA) is a key regulator of the host circadian clock. This work also demonstrates that gut microbe-targeted enzyme inhibitors have potential as anti-obesity therapeutics.
Asunto(s)
Colina/análogos & derivados , Ritmo Circadiano/efectos de los fármacos , Microbioma Gastrointestinal/efectos de los fármacos , Obesidad/metabolismo , Animales , Colina/administración & dosificación , Colina/metabolismo , Dieta Alta en Grasa , Inhibidores Enzimáticos/farmacología , Leptina/deficiencia , Liasas/efectos de los fármacos , Masculino , Metilaminas/metabolismo , Ratones , Ratones Endogámicos C57BL , Obesidad/genética , Obesidad/microbiologíaRESUMEN
Lipodystrophy syndromes are rare complex multisystem disorders caused by generalized or partial lack of adipose tissue. Adipose tissue dysfunction in lipodystrophy is associated with leptin deficiency. Lipodystrophy leads to severe metabolic problems. These abnormalities include, but are not limited to, insulin-resistant diabetes, severe hypertriglyceridemia, and lipid accumulation in ectopic organs such as the liver, and are associated with end-organ complications. Metabolic abnormalities can be present at the time of diagnosis or may develop over time as the disease progresses. In addition to metabolic abnormalities, subtype-specific presentations due to underlying molecular etiology in genetic forms and autoimmunity in acquired forms contribute to severe morbidity in lipodystrophy.
Asunto(s)
Leptina/deficiencia , Lipodistrofia/complicaciones , Enfermedades Autoinmunes/etiología , Diabetes Mellitus/etiología , Cardiopatías/genética , Humanos , Hipertrigliceridemia/etiología , Resistencia a la Insulina , Enfermedades Renales/complicaciones , Metabolismo de los Lípidos , Lipodistrofia/genética , Lipodistrofia/metabolismo , Lipodistrofia/mortalidad , Hígado/metabolismo , Síndrome Metabólico/etiología , Enfermedades Neuromusculares/etiología , Enfermedad del Hígado Graso no Alcohólico/etiología , Pancreatitis/etiología , SíndromeRESUMEN
Lipodystrophy syndromes (LS) constitute a group of rare diseases of the adipose tissue, characterized by a complete or selective deficiency of the fat mass. These disorders are associated with important insulin resistance, cardiovascular and metabolic comorbidities that impact patient's survival and quality of life. Management is challenging and includes diet, physical activity, and specific pharmacological treatment of LS-associated comorbidities. Because of a common pathophysiology involving decreased concentration of the adipokine leptin, efforts have been made to develop therapeutic strategies with leptin replacement therapy. Metreleptin, a recombinant human leptin analogue, has been proposed in hypoleptinemic patients since the beginning of 2000's. The treatment leads to an improvement in metabolic parameters, more important in generalized than in partial LS forms. In this review, the current knowledge about the development of the drug, its outcomes in the treatment of lipodystrophic patients as well as the peculiarities of its use will be presented.
Asunto(s)
Leptina/análogos & derivados , Lipodistrofia/terapia , Enfermedades Autoinmunes/terapia , Huesos/efectos de los fármacos , Dislipidemias/terapia , Hígado Graso/terapia , Glucosa/metabolismo , Humanos , Hiperglucemia/terapia , Hipertensión/terapia , Riñón/efectos de los fármacos , Leptina/efectos adversos , Leptina/deficiencia , Leptina/fisiología , Leptina/uso terapéutico , Metabolismo de los Lípidos/efectos de los fármacos , Calidad de Vida , Proteínas Recombinantes/uso terapéutico , Reproducción/efectos de los fármacos , SíndromeRESUMEN
Obesity is a pandemic condition of complex etiology, resulting from the increasing exposition to obesogenic environmental factors combined with genetic susceptibility. In the past two decades, advances in genetic research identified variants of the leptin-melanocortin pathway coding for genes, which are related to the potentiation of satiety and hunger, immune system, and fertility. Here, we review cases of congenital leptin deficiency and the possible beneficial effects of leptin replacement therapy. In summary, the cases presented here show clinical phenotypes of disrupted bodily energy homeostasis, biochemical and hormonal disorders, and abnormal immune response. Some phenotypes can be partially reversed by exogenous administration of leptin. With this review, we aim to contribute to the understanding of leptin gene mutations as targets for obesity diagnostics and treatment strategies.
Asunto(s)
Leptina/uso terapéutico , Obesidad/tratamiento farmacológico , Obesidad/genética , Metabolismo Energético/genética , Terapia de Reemplazo de Hormonas , Humanos , Leptina/deficiencia , Leptina/genética , Mutación , Obesidad/congénito , FenotipoRESUMEN
Leptin is a principal adipose-derived hormone mostly implicated in the regulation of energy balance through the activation of anorexigenic neuronal pathways. Comprehensive studies have established that the maintenance of certain concentrations of circulating leptin is essential to avoid an imbalance in nutrient intake. Indeed, genetic modifications of the leptin/leptin receptor axis and the obesogenic environment may induce changes in leptin levels or action in a manner that accelerates metabolic dysfunctions, resulting in a hyperphagic status and adipose tissue expansion. As a result, a vicious cycle begins wherein hyperleptinaemia and leptin resistance occur, in turn leading to increased food intake and fat enlargement, which is followed by leptin overproduction. In addition, in the context of obesity, a defective thermoregulatory response is associated with impaired leptin signalling overall within the ventromedial nucleus of the hypothalamus. These recent findings highlight the role of leptin in the regulation of adaptive thermogenesis, thus suggesting leptin to be potentially considered as a new thermolipokine. This review provides new insight into the link between obesity, hyperleptinaemia, leptin resistance and leptin deficiency, focusing on the ability to restore leptin sensitiveness by way of enhanced thermogenic responses and highlighting novel anti-obesity therapeutic strategies.
Asunto(s)
Leptina/metabolismo , Obesidad/metabolismo , Transducción de Señal , Animales , Biomarcadores , Regulación de la Temperatura Corporal , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Metabolismo Energético , Humanos , Hipotálamo/metabolismo , Leptina/sangre , Leptina/deficiencia , Obesidad/diagnóstico , Obesidad/etiología , Obesidad/terapia , Termogénesis , Resultado del TratamientoRESUMEN
BACKGROUND: Obesity-associated asthma is a phenotype of severe asthma. Late-onset, non-eosinophilic and female-dominant phenotype is highly symptomatic and difficult to treat. Leptin, an adipokine, exerts an immunomodulatory effect. IL-33 associated with innate immunity induces type 2 inflammation and is present in adipose tissue. The purpose of this study was to elucidate the pathogenesis of obesity-associated asthma by focusing on the interaction between leptin and IL-33. METHODS: In leptin-deficient obese (ob/ob) and wild-type mice, IL-33 was instilled intranasally on three consecutive days. In part of the mice, leptin was injected intraperitoneally prior to IL-33 treatment. The mice were challenged with methacholine, and airway hyperresponsiveness (AHR) was assessed by resistance (Rrs) and elastance (Ers) of the respiratory system using the forced oscillation technique. Cell differentiation, IL-5, IL-13, eotaxin, keratinocyte-derived chemokine (KC) in bronchoalveolar lavage fluid (BALF) and histology of the lung were analyzed. For the in vitro study, NCI-H292 cells were stimulated with IL-33 in the presence or absence of leptin. Mucin-5AC (MUC5AC) levels were measured using an enzyme-linked immunosorbent assay. RESULTS: Ob/ob mice showed greater Rrs and Ers than wild-type mice. IL-33 with leptin, but not IL-33 alone, enhanced Ers rather than Rrs challenged with methacholine in ob/ob mice, whereas it enhanced Rrs alone in wild-type mice. IL-33-induced eosinophil numbers, cytokine levels in BALF, eosinophilic infiltration around the bronchi, and goblet cell metaplasia were less in ob/ob mice than in wild-type mice. However, leptin pretreatment attenuated these changes in ob/ob mice. MUC5AC levels were increased by co-stimulation with IL-33 and leptin in vitro. CONCLUSIONS: Ob/ob mice show innate AHR. IL-33 with leptin, but not IL-33 alone, induces airway inflammation and goblet cell metaplasia and enhances AHR involving peripheral airway closure. This is presumably accelerated by mucus in ob/ob mice. These results may explain some aspects of the pathogenesis of obesity-associated asthma.
Asunto(s)
Asma/patología , Bronquios/patología , Células Caliciformes/patología , Inflamación/patología , Leptina/deficiencia , Obesidad/complicaciones , Animales , Asma/inducido químicamente , Asma/complicaciones , Bronquios/metabolismo , Líquido del Lavado Bronquioalveolar/citología , Modelos Animales de Enfermedad , Femenino , Células Caliciformes/metabolismo , Inflamación/metabolismo , Interleucina-33/toxicidad , Leptina/metabolismo , Metaplasia , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/metabolismo , Obesidad/patologíaRESUMEN
SUMMARY: Nonalcoholic fatty liver disease (NAFLD) might progress the steatosis to nonalcoholic steatohepatitis (NASH), reaching a cirrhosis state and possibly hepatocellular carcinoma. The liver of three-month-old C57BL/6J mice (wild-type, WT group, n=10) and leptin- deficient obese mice (ob/ob group, n=10) were studied, focusing on the mechanisms associated with the activation of the hepatic stellate cells (HSCs) and pro-fibrogenesis. The obese ob/ob animals' liver showed steatosis, increased lipogenesis gene expressions, inflammation, increased pro-inflammatory gene expressions, inflammatory infiltrate, and potential apoptosis linked to a high Caspase 3 expression. In ob/ob mice, liver sections were labeled in the fibrotic zones by anti-alpha-smooth muscle actin (alpha-SMA) and anti-Reelin, but not in the WT mice. Moreover, the alpha-SMA gene expression was higher in the ob/ob group's liver than the WT group. The pro-fibrogenic gene expressions were parallel to anti- alpha-SMA and anti-Reelin immunofluorescence, suggesting HSCs activation. In the ob/ob animals, there were increased gene expressions involved with lipogenesis (Peroxisome proliferator-activated receptor-gamma, Cell death-inducing DFFA-like effector-c, Sterol regulatory element-binding protein-1c, and Fatty acid synthase), pro-fibrogenesis (Transforming growth factor beta1, Smad proteins- 3, Yes-associated protein-1, Protein platelet-derived growth factor receptor beta), pro-inflammation (Tumor necrosis factor-alpha, and Interleukin-6), and apoptosis (Caspase 3). In conclusion, the results in obese ob/ob animals provide a clue to the events in humans. In a translational view, controlling these targets can help mitigate the hepatic effects of human obesity and NAFLD progression to NASH.
RESUMEN: La enfermedad del hígado graso no alcohólico (HGNA) puede progresar de la esteatosis a esteatohepatitis no alcohólica (ENA), alcanzando un estado de cirrosis y posiblemente carcinoma hepatocelular. Se estudió el hígado de ratones C57BL / 6J de tres meses de edad (tipo salvaje, grupo WT, n = 10) y ratones obesos con deficiencia de leptina (grupo ob/ob, n = 10), centrándose en los mecanismos asociados con la activación de las células estrelladas hepáticas (HSC) y profibrogénesis. El hígado de los animales obesos ob/ob mostró esteatosis, aumento de la expresión génica de la lipogénesis, inflamación, aumento de la expresión génica proinflamatoria, infiltrado inflamatorio y posible apoptosis ligada a una alta expresión de Caspasa 3. En ratones ob/ob, las sec- ciones de hígado se marcaron en las zonas fibróticas con anti-alfa- actina de músculo liso (alfa-SMA) y anti-Reelin, pero no en los ratones WT. Además, la expresión del gen alfa-SMA fue mayor en el hígado del grupo ob/ob que en el grupo WT. Las expresiones génicas profibrogénicas fueron paralelas a la inmunofluorescencia anti-alfa-SMA y anti-Reelin, lo que sugiere la activación de las HSC. En los animales ob/ob, hubo un aumento de las expresiones génicas involucradas con la lipogénesis (receptor activado por proliferador de peroxisoma gamma, efector c similar a DFFA inductor de muerte celular, proteína de unión al elemento regulador de esterol-1c y sintasa de ácidos grasos), pro-fibrogénesis (factor de crecimiento transformante beta 1, proteínas Smad-3, proteína-1 asociada a Yes, receptor beta del factor de crecimiento derivado de plaquetas de proteínas), proinflamación (factor de necrosis tumoral alfa e interleucina-6) y apoptosis (caspasa 3). ). En conclusión, los resultados en animales obesos ob/ob proporcionan una pista de los eventos en humanos. Desde un punto de vista traslacional, el control de estos objetivos puede ayudar a mitigar los efectos hepáticos de la obesidad humana y la progresión de HGNA a ENA.
Asunto(s)
Animales , Ratones , Leptina/deficiencia , Hígado Graso/patología , Fotomicrografía , Apoptosis , Microscopía Confocal , Lipogénesis/genética , Caspasa 3/metabolismo , Células Estrelladas Hepáticas/ultraestructura , Hígado Graso/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Enfermedad del Hígado Graso no Alcohólico/patología , Inflamación/genética , Hígado/ultraestructura , Cirrosis Hepática/genética , Cirrosis Hepática/patología , Ratones Endogámicos C57BL , ObesidadRESUMEN
Follicular helper T (TFH) cells control antibody responses by supporting antibody affinity maturation and memory formation. Inadequate TFH function has been found in individuals with ineffective responses to vaccines, but the mechanism underlying TFH regulation in vaccination is not understood. Here, we report that lower serum levels of the metabolic hormone leptin associate with reduced vaccine responses to influenza or hepatitis B virus vaccines in healthy populations. Leptin promotes mouse and human TFH differentiation and IL-21 production via STAT3 and mTOR pathways. Leptin receptor deficiency impairs TFH generation and antibody responses in immunisation and infection. Similarly, leptin deficiency induced by fasting reduces influenza vaccination-mediated protection for the subsequent infection challenge, which is mostly rescued by leptin replacement. Our results identify leptin as a regulator of TFH cell differentiation and function and indicate low levels of leptin as a risk factor for vaccine failure.
Asunto(s)
Formación de Anticuerpos/inmunología , Vacunas contra la Influenza/inmunología , Leptina/metabolismo , Animales , Anticuerpos Antivirales/inmunología , Diferenciación Celular , Femenino , Homeostasis , Humanos , Inmunización , Gripe Humana/prevención & control , Leptina/deficiencia , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Vacunación/métodosRESUMEN
BACKGROUND: Evidence from in vitro and rodent studies suggests that leptin, a key signal of long-term energy reserves, promotes IGF1 synthesis and linear growth. This effect of leptin has not been fully investigated in humans. The aim of our study was to investigate the effect of leptin substitution on growth factors and linear growth in children with congenital leptin deficiency (CLD). METHODS: In this cohort study we included eight pediatric patients (six males), age 0.9-14.8 years, who were diagnosed with CLD and received leptin substitution at our University Medical Center. We calculated standard deviation scores (SDS) for serum levels of IGF1 and IGFBP3, IGF1/IGFBP3 molar ratio, and height at baseline (T0) and 12 months (T12) after the initiation of substitution with metreleptin. RESULTS: All patients had severe obesity (BMI-SDS mean ± SD: 4.14 ± 1.51) at T0 and significant BMI-SDS reduction to 2.47 ± 1.05 at T12. At T0, all patients were taller than the mid-parental median, yet had low IGF1 and IGF1/IGFBP3 molar ratios (IGF1-SDS[Formula: see text]T0: -1.58 ± 0.92, IGF1/IGFBP3 molar ratio-SDS[Formula: see text]T0: -1.58 ± 0.88). At T12, IGF1-SDS increased significantly (∆T0-12: 1.63 ± 1.40, p = 0.01), and IGFBP3-SDS and IGF1/IGFBP3 molar ratio-SDS showed a trend toward an increase. In the three children within the childhood growth period (post-infancy, pre-puberty) height-SDS increased (∆height-SDST0-12: 0.57 ± 0.06, p = 0.003) despite substantial weight loss. CONCLUSIONS: These results in CLD patients are contrary to observations in children with idiopathic obesity who typically have above-mean IGF1 levels that decrease with weight loss, and therefore suggest that leptin increases IGF1 levels and promotes linear growth.
Asunto(s)
Enfermedades Carenciales , Factor I del Crecimiento Similar a la Insulina/análisis , Leptina , Adolescente , Niño , Preescolar , Estudios de Cohortes , Enfermedades Carenciales/sangre , Enfermedades Carenciales/tratamiento farmacológico , Enfermedades Carenciales/genética , Enfermedades Carenciales/fisiopatología , Femenino , Humanos , Lactante , Leptina/administración & dosificación , Leptina/deficiencia , Leptina/uso terapéutico , MasculinoRESUMEN
In much of the developing world, severe malnutrition is the most prevalent cause of immunodeficiency and affects up to 50% of the population in some impoverished communities. As yet, we do not know how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will behave in populations with immunodeficiency caused by malnourishment. Interestingly, researchers are now speculating that, in some instances, a defective cellular immune system could paradoxically be a protective factor against severe disease in certain patients contracting SARS-CoV and SARS-CoV-2. This could be linked to the absence of T-cell activation. Based on available information presented here, it is plausible that the hyperimmune response, and subsequent cytokine storm often associated with severe coronavirus disease 2019 (COVID-19), could be "counteracted" by the defective immune response seen in individuals with malnutrition-induced leptin deficiency. In this paper, we proposed a theory that although those with malnutrition-linked leptin deficiency are at risk of SARS-CoV-2 infection, they are at lower risk of developing severe COVID-19.
Asunto(s)
COVID-19/complicaciones , Leptina/deficiencia , Desnutrición/complicaciones , SARS-CoV-2 , Formación de Anticuerpos , Índice de Masa Corporal , Vacunas contra la COVID-19/inmunología , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/prevención & control , Países en Desarrollo , Susceptibilidad a Enfermedades , Humanos , Inmunidad Celular , Inmunogenicidad Vacunal , Síndromes de Inmunodeficiencia/etiología , Leptina/fisiología , Activación de Linfocitos , Desnutrición/inmunología , Modelos Biológicos , Obesidad/complicaciones , Desnutrición Proteico-Calórica/complicaciones , Desnutrición Proteico-Calórica/inmunología , Riesgo , Índice de Severidad de la Enfermedad , Linfocitos T/inmunologíaRESUMEN
BACKGROUND: Infections and sepsis are common causes of morbidity and mortality, with an increasing incidence worldwide. Leptin is involved in the inflammatory process and may modulate the cytokine production, immune cell proliferation and endothelial function. There are conflicting results regarding alterations of leptin levels in infectious diseases and the outcome from sepsis.The aim of the current article is to provide an overview of the medical literature on the correlations between variations of leptin levels and infectious diseases and sepsis. METHODS: We performed an extensive literature search in PubMed and Google Scholar databases, using keywords to identify articles related to leptin in infectious diseases and sepsis. Searches were referenced using medical subject headings that included "leptin," "adipokines," "sepsis," "infectious diseases," "leptin deficiency," "leptin resistance" or "hyperleptinemia." The language of publication, journal, or country were not included as limitation criteria.Articles or abstracts containing adequate information, such as age, sex, anthropometric indices, clinical presentation, comorbidities, and management were included in the study, whereas articles with insufficient clinical and demographic data were excluded. We assessed the quality of the studies selected.The final review of all databases was conducted on June 18, 2020. RESULTS: We find the results from the current review to be of great importance due to the possible therapeutic role of leptin analogs in states of leptin deficiency associated with infectious diseases or sepsis.In hyperleptinemia, a therapeutic plan for obtaining leptin neutralization also needs further investigations. This could lead to the reduction of proinflammatory responses.There is a need for further studies to demonstrate the specificity and sensitivity of leptin in the early diagnosis of sepsis and the need to measure serum leptin levels in routine evaluation of the critical patient. CONCLUSION: The multiple effects of leptin are of growing interest, but further studies are needed to elucidate the role of leptin signalling in infectious diseases and sepsis. Because very few human studies are reported, we recommend the need for further research.Better understanding of the pathophysiology of sepsis and the implication of circulating total leptin in this process could help physicians in managing this life-threatening condition.
Asunto(s)
Enfermedades Transmisibles , Leptina , Sepsis , Enfermedades Transmisibles/sangre , Enfermedades Transmisibles/inmunología , Descubrimiento de Drogas/métodos , Diagnóstico Precoz , Humanos , Leptina/análogos & derivados , Leptina/antagonistas & inhibidores , Leptina/sangre , Leptina/deficiencia , Pronóstico , Sepsis/sangre , Sepsis/diagnóstico , Sepsis/inmunologíaRESUMEN
BACKGROUND: The gut microbiota plays a role in the occurrence of nonalcoholic fatty liver disease (NAFLD), notably through the production of bioactive metabolites. Indole, a bacterial metabolite of tryptophan, has been proposed as a pivotal metabolite modulating inflammation, metabolism, and behavior. OBJECTIVES: The aim of our study was to mimic an upregulation of intestinal bacterial indole production and to evaluate its potential effect in vivo in 2 models of NAFLD. METHODS: Eight-week-old leptin-deficient male ob/ob compared with control ob/+ mice (experiment 1), and 4-5-wk-old C57BL/6JRj male mice fed a low-fat (LF, 10 kJ%) compared with a high-fat (HF, 60 kJ%) diet (experiment 2), were given plain water or water supplemented with a physiological dose of indole (0.5 mM, n ≥6/group) for 3 wk and 3 d, respectively. The effect of the treatments on the liver, intestine, adipose tissue, brain, and behavior was assessed. RESULTS: Indole reduced hepatic expression of genes involved in inflammation [C-C motif chemokine ligand 2 (Ccl2), C-X-C motif chemokine ligand 2 (Cxcl2); 3.3- compared with 5.0-fold, and 2.4- compared with 3.3-fold of control ob/+ mice, respectively, P < 0.05], and in macrophage activation [Cd68, integrin subunit α X (Itgax); 2.1- compared with 2.5-fold, and 5.0- compared with 6.4-fold of control ob/+ mice, respectively, P < 0.01] as well as markers of hepatic damage (alaninine aminotransferase; -32%, P < 0.001) regardless of genotype in experiment 1. Indole had no effect on hepatic inflammation in mice fed the LF or HF diet in experiment 2. Indole did not change hepatic lipid content, anxiety-like behavior, or inflammation in the ileum, adipose tissue, and brain in experiment 1. CONCLUSIONS: Our results support the efficacy of indole to reduce hepatic damage and associated inflammatory response and macrophage activation in ob/ob mice. These modifications appear to be attributable to direct effects of indole on the liver, rather than through effects on the adipose tissue or intestinal barrier.
Asunto(s)
Microbioma Gastrointestinal , Indoles , Leptina/deficiencia , Enfermedad del Hígado Graso no Alcohólico , Animales , Quimiocina CCL2 , Quimiocina CXCL2 , Dieta Alta en Grasa , Indoles/farmacología , Inflamación , Ligandos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Sustancias Protectoras/farmacologíaRESUMEN
Leptin is a hormone which functions in the regulation of energy homeostasis via suppression of appetite. In zebrafish, there are two paralogous genes encoding leptin, called lepa and lepb. In a gene expression study, we found that the lepb gene, not the lepa gene, was significantly downregulated under the state of insulin-resistance in zebrafish larvae, suggesting that the lepb plays a role in glucose homeostasis. In the current study, we characterised lepb-deficient (lepb-/-) adult zebrafish generated via a CRISPR-CAS9 gene editing approach by investigating whether the disruption of the lepb gene would result in the development of type 2 diabetes mellitus (T2DM) and diabetic complications. We observed that lepb-/- adult zebrafish had an increase in body weight, length and visceral fat accumulation, compared to age-matched control zebrafish. In addition, lepb-/- zebrafish had significantly higher blood glucose levels compared to control zebrafish. These data collectively indicate that lepb-/- adult zebrafish display the features of T2DM. Furthermore, we showed that lepb-/- adult zebrafish had glomerular hypertrophy and thickening of the glomerular basement membrane, compared to control zebrafish, suggesting that lepb-/- adult zebrafish develop early signs of diabetic nephropathy. In conclusion, our results demonstrate that lepb regulates glucose homeostasis and adiposity in zebrafish, and suggest that lepb-/- mutant zebrafish are a promising model to investigate the role of leptin in the development of T2DM and are an attractive model to perform mechanistic and therapeutic research in T2DM and its complications.