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1.
Physiol Biochem Zool ; 96(1): 30-39, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36626840

RESUMO

AbstractLeptin is recognized as an anorexigenic hormone. In its absence (e.g., in ob/ob mutant mice), mice become obese, primarily as a result of hyperphagia. A recurrent question is whether, additionally, leptin is thermogenic and thus also an antiobesity hormone in this way. We have earlier reviewed available data and have concluded that most articles implying a thermogenic effect of leptin have based this on a misconstrued division by body weight. Here, we have collected evidence that the remaining observations that imply that leptin is a thermogenic hormone are better understood as implying that leptin is an antitorpor hormone. Leptin levels increase in proportion to the body's energy reserves (i.e., stored lipids in the adipose tissue), and leptin thus serves as an indicator of energy availability. In the absence of leptin, ob/ob mice are exceedingly prone to enter daily torpor, since the absence of leptin causes them to perceive a lack of body energy reserves that, in combination with restricted or no food, induces them to enter the torpid state to save energy. This antitorpor effect of leptin probably explains the following earlier observations. First, ob/ob mice have the ability to gain weight even when pair fed with leptin-treated ob/ob mice. This is understood as follows: In the leptin-treated ob/ob mice, food intake is reduced. Untreated pair-fed mice enter daily torpor, and this markedly lowers total daily energy expenditure; the resulting surplus food energy is then accumulated as fat in these mice. However, ob/ob mice fed ad lib. do not enter torpor, so under normal conditions this mechanism does not contribute to the obesity found in the ob/ob mice. Second, neonatal ob/ob mice have the ability to become obese despite eating the same amount as wild-type mice: this is understood as these mice similarly entering daily torpor. Third, ob/ob mice on the C57BL/6J background have a lower metabolic rate: these mice were examined in the absence of food, and torpor was thus probably induced. Fourth, ob/ob mice have apparent high cold sensitivity: these mice experienced cold in the absence of food and would immediately enter deep torpor. It is suggested that this novel explanation of how the antitorpor effects of leptin affect mouse energy metabolism can open new avenues for leptin research.


Assuntos
Leptina , Obesidade , Animais , Camundongos , Tecido Adiposo/metabolismo , Peso Corporal , Metabolismo Energético , Leptina/metabolismo , Leptina/farmacologia , Camundongos Endogâmicos C57BL , Obesidade/metabolismo
2.
Nutrients ; 15(2)2023 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-36678304

RESUMO

(1) Background: Adequate protein intake plays an essential role in growth and neurodevelopment, especially in preterm infants. We investigated the effects of maternal diet and body mass index (BMI) on human milk (HM) composition. (2) Methods: HM samples were obtained from 136 lactating mothers (BMI: 18.0-36.7 kg/m2), of which 93% gave birth to preterm infants. Macronutrient content in HM was measured by mid-infrared transmission spectroscopy. Leptin and adiponectin were analyzed using appropriate ELISAs. Maternal diet was determined by 24-h recall. (3) Results: Significant positive associations were found between protein, fat, carbohydrate and energy intake, and levels of corresponding macronutrients in HM, especially in protein concentrations (p < 0.001). An increased protein intake was positively correlated with adiponectin (p < 0.001) and leptin (p = 0.035) in HM. Maternal BMI was positively associated with a higher protein level in HM (p < 0.05), as well as with a higher dietary protein intake (p < 0.05). (4) Conclusions: Knowledge of maternal diet and BMI impacting HM composition is essential to optimize the feeding of newborn infants. This is especially relevant in the nutritional management of preterm infants; it can be utilized in approaches to improve growth rates and the appropriate development of infants and to prevent obesity.


Assuntos
Leptina , Leite Humano , Lactente , Feminino , Humanos , Recém-Nascido , Leite Humano/química , Leptina/metabolismo , Recém-Nascido Prematuro , Lactação , Adiponectina/metabolismo , Proteínas na Dieta/metabolismo , Dieta , Tecido Adiposo , Proteínas do Leite/análise , Aleitamento Materno
3.
Int J Mol Sci ; 24(2)2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36674935

RESUMO

Excess body weight is frequently associated with low-grade inflammation. Evidence indicates a relationship between obesity and cancer, as well as with other diseases, such as diabetes and non-alcoholic fatty liver disease, in which inflammation and the actions of various adipokines play a role in the pathological mechanisms involved in these disorders. Leptin is mainly produced by adipose tissue in proportion to fat stores, but it is also synthesized in other organs, where leptin receptors are expressed. This hormone performs numerous actions in the brain, mainly related to the control of energy homeostasis. It is also involved in neurogenesis and neuroprotection, and central leptin resistance is related to some neurological disorders, e.g., Parkinson's and Alzheimer's diseases. In peripheral tissues, leptin is implicated in the regulation of metabolism, as well as of bone density and muscle mass. All these actions can be affected by changes in leptin levels and the mechanisms associated with resistance to this hormone. This review will present recent advances in the molecular mechanisms of leptin action and their underlying roles in pathological situations, which may be of interest for revealing new approaches for the treatment of diseases where the actions of this adipokine might be compromised.


Assuntos
Leptina , Obesidade , Humanos , Leptina/metabolismo , Obesidade/metabolismo , Adipocinas/metabolismo , Tecido Adiposo/metabolismo , Inflamação/metabolismo
4.
Nat Metab ; 5(1): 147-164, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36593271

RESUMO

Leptin acts on hypothalamic neurons expressing agouti-related protein (AgRP) or pro-opiomelanocortin (POMC) to suppress appetite and increase energy expenditure, but the intracellular mechanisms that modulate central leptin signalling are not fully understood. Here we show that growth factor receptor-bound protein 10 (Grb10), an adaptor protein that binds to the insulin receptor and negatively regulates its signalling pathway, can interact with the leptin receptor and enhance leptin signalling. Ablation of Grb10 in AgRP neurons promotes weight gain, while overexpression of Grb10 in AgRP neurons reduces body weight in male and female mice. In parallel, deletion or overexpression of Grb10 in POMC neurons exacerbates or attenuates diet-induced obesity, respectively. Consistent with its role in leptin signalling, Grb10 in AgRP and POMC neurons enhances the anorexic and weight-reducing actions of leptin. Grb10 also exaggerates the inhibitory effects of leptin on AgRP neurons via ATP-sensitive potassium channel-mediated currents while facilitating the excitatory drive of leptin on POMC neurons through transient receptor potential channels. Our study identifies Grb10 as a potent leptin sensitizer that contributes to the maintenance of energy homeostasis by enhancing the response of AgRP and POMC neurons to leptin.


Assuntos
Leptina , Pró-Opiomelanocortina , Camundongos , Masculino , Feminino , Animais , Proteína Relacionada com Agouti/metabolismo , Leptina/metabolismo , Pró-Opiomelanocortina/metabolismo , Proteína Adaptadora GRB10/metabolismo , Redução de Peso
5.
Nat Neurosci ; 26(1): 79-91, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36510113

RESUMO

Early-life trauma (ELT) is a risk factor for binge eating and obesity later in life, yet the neural circuits that underlie this association have not been addressed. Here, we show in mice that downregulation of the leptin receptor (Lepr) in the lateral hypothalamus (LH) and its effect on neural activity is crucial in causing ELT-induced binge-like eating and obesity upon high-fat diet exposure. We also found that the increased activity of Lepr-expressing LH (LHLepr) neurons encodes sustained binge-like eating in ELT mice. Inhibition of LHLepr neurons projecting to the ventrolateral periaqueductal gray normalizes these behavioral features of ELT mice. Furthermore, activation of proenkephalin-expressing ventrolateral periaqueductal gray neurons, which receive inhibitory inputs from LHLepr neurons, rescues ELT-induced maladaptive eating habits. Our results identify a circuit pathway that mediates ELT-induced maladaptive eating and may lead to the identification of novel therapeutic targets for binge eating and obesity.


Assuntos
Região Hipotalâmica Lateral , Leptina , Camundongos , Animais , Leptina/metabolismo , Região Hipotalâmica Lateral/metabolismo , Comportamento Alimentar , Obesidade/metabolismo , Substância Cinzenta Periaquedutal , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Ingestão de Alimentos
6.
Neurosci Lett ; 793: 136996, 2023 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-36481371

RESUMO

Leptin receptors (LepR) are expressed in brain areas controlling food intake homeostasis, such as the hypothalamus, the hippocampus and the prefrontal cortex. In a previous study we reported that long-term intake of saturated and monounsaturated fat alters hypothalamic LepR signalling. The current study aims at investigating the effect of foods high in either saturated (SOLF) or monounsaturated fat (UOLF) on LepR functionality in the hippocampus and the prefrontal cortex. Male mice were placed on SOLF/UOLF (eight weeks), then treated with recombinant murine leptin (1 mg/kg). After 60 min, brain regions were dissected and processed for western blot of phosphorylated STAT3 (pSTAT3), Akt (pAkt) and AMPK (pAMPK). Levels of SOCS3 were also quantified. SOLF itself increased basal levels of pSTAT3, while UOLF impaired leptin-induced phosphorylation of both Akt and AMPK. SOCS3 levels were specifically increased by UOLF within the prefrontal cortex. Our results show that SOLF and UOLF differently affect LepR signalling within the hippocampus and the prefrontal cortex, which points to the complex effect of saturated and unsaturated fat on brain function, particularly in areas regulating food intake.


Assuntos
Encéfalo , Receptores para Leptina , Animais , Masculino , Camundongos , Proteínas Quinases Ativadas por AMP , Encéfalo/metabolismo , Gorduras Insaturadas/administração & dosagem , Hipotálamo/metabolismo , Leptina/metabolismo , Proteínas Proto-Oncogênicas c-akt , Receptores para Leptina/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo
7.
Eur J Med Chem ; 245(Pt 1): 114927, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36379105

RESUMO

Adiponectin and leptin are major adipocytokines that control crosstalk between adipose tissue and other organ systems. Hypoadiponectinemia and hypoleptinemia are associated with human metabolic diseases. Compounds with adipocytokine biosynthesis-stimulating activities could be developed as therapeutics against diverse metabolic conditions. In phenotypic screening with human bone marrow mesenchymal stem cells (hBM-MSCs), (E)-4-hydroxy-3-(3-(4-hydroxy-3-methoxyphenyl)acryloyl)-6-methyl-2H-pyran-2-one (1) was identified to increase adiponectin biosynthesis during adipogenesis and simultaneously to stimulate leptin production. Using the compound 1 structure, the structure-activity relationship study was performed to discover more potent compounds stimulating both adiponectin and leptin production. (E)-3-(3-(2-fluoropyridin-4-yl)acryloyl)-4-hydroxy-6-methyl-2H-pyran-2-one (11) exhibited the most potent adiponectin (EC50, 2.87 µM) and leptin (EC50, 2.82 µM) biosynthesis-stimulating activities in hBM-MSCs. In a target identification study, compound 11 was characterized as a dual modulator binding to both peroxisome proliferator-activated receptor (PPAR) γ and glucocorticoid receptor (GR). This study provides a novel pharmacophore for PPARγ/GR dual modulators with therapeutic potential against human metabolic diseases.


Assuntos
Adiponectina , Leptina , Células-Tronco Mesenquimais , PPAR gama , Piranos , Receptores de Glucocorticoides , Humanos , Adipogenia , Adiponectina/biossíntese , Leptina/farmacologia , Leptina/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , PPAR gama/agonistas , Piranos/química , Piranos/farmacologia , Receptores de Glucocorticoides/agonistas
9.
BMC Complement Med Ther ; 22(1): 316, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36456983

RESUMO

BACKGROUND: Accumulating evidence reveals that music therapy appears to help patients with pain. However, there is a limited understanding of the underlying mechanisms. Several studies indicate that leptin level has a crucial relationship with acute and chronic pain. Herein, we evaluated the effects of music stimulation and the potential roles of adipokines (leptin) in pain behaviors. METHODS: We used a tibial neuroma transposition (TNT) rat model to mimic neuroma pain. Adult male Sprague-Dawley rats were randomly assigned to one of the three groups (n = 6):group 1 (GC), TNT with white noise; group 2(GM), TNT with music; and group 3(GH), TNT. White noise and music stimulation was given once a day following surgery until the end of the study (42nd day). Pain behavioral tests were carried out before surgery and on the 3rd, 10th, 14th, 21st, 28th, 35th, and 42nd days after surgery. At the end of the observation period, we analyzed the histological samples of blood, spinal cord, and prefrontal cortex to investigate the role of leptin in pain behaviors modulated by white noise and sound stimulation. RESULT: Music therapy might improve the pain of TNT rats. Music stimulation ameliorated paw withdrawal thermal latency (PWTL) from the 3rd day after the surgery while the mechanical pain was improved 21 days after the operation.Music stimulation also increased leptin expression in the spinal cord, prefrontal cortex.White noise had no obvious effect. CONCLUSION: Music therapy might improve the pain of TNT rats. Besides, music stimulation ameliorated TNT-induced pain behaviors and affected leptin expression.


Assuntos
Leptina , Musicoterapia , Neuroma , Manejo da Dor , Animais , Masculino , Ratos , Leptina/metabolismo , Neuroma/complicações , Neuroma/terapia , Dor , Ratos Sprague-Dawley , Manejo da Dor/métodos
10.
Biomed Khim ; 68(6): 427-436, 2022 Dec.
Artigo em Russo | MEDLINE | ID: mdl-36573409

RESUMO

Functional disorders in obesity are largely due to a decrease in tissue sensitivity to insulin and leptin. One of the ways to restore it is inhibition of protein phosphotyrosine phosphatase 1B (PTP1B) and T-cell protein phosphotyrosine phosphatase (TCPTP), negative regulators of the insulin and leptin signaling. Despite progress in the development of inhibitors of these phosphatases, commercial preparations based on them have not been developed yet, and the mechanisms of action are poorly understood. The aim of the work was to study the effect of new derivatives of 4-oxo-1,4-dihydrocinnoline (PI04, PI06, PI07) on the activity of PTP1B and TCPTP, as well as to study the effect of their five-day administration (i.p., 10 mg/kg/day) to Wistar rats with diet-induced obesity on body weight and fat, metabolic and hormonal parameters, and gene expression of phosphatase and insulin and leptin receptors in the liver. It has been shown that PI04 is a mild, low selective inhibitor of both phosphatases (PTP1B, IC50=3.42(2.60-4.51) µM; TCPTP, IC50=4.16(3.49-4.95) µM), while PI06 and PI07 preferentially inhibit PTP1B (IC50=3.55 (2.63-4.78) µM) and TCPTP (IC50=1.45(1.18-1.78) µM), respectively. PI04 significantly reduced food intake, body weight and fat, attenuated hyperglycemia, normalized glucose tolerance, basal and glucose-stimulated levels of insulin and leptin, and insulin resistance index. Despite the anorexigenic effect, PI06 and PI07 were less effective, having little effect on glucose homeostasis and insulin sensitivity. PI04 significantly increased the expression of the PTP1B and TCPTP genes and decreased the expression of the insulin and leptin receptor genes. PI06 and PI07 had little effect on these indicators. Thus, PI04, the inhibitor of PTP1B and TCPTP phosphatases, restored metabolic and hormonal parameters in obese rats with greater efficiency than inhibitors of PTP1B (PI06) and TCPTP (PI07). This indicates the prospect of creating mixed PTP1B/TCPTP inhibitors for correction of metabolic disorders.


Assuntos
Resistência à Insulina , Leptina , Animais , Ratos , Inibidores Enzimáticos/farmacologia , Glucose/metabolismo , Insulina/metabolismo , Leptina/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Proteína Tirosina Fosfatase não Receptora Tipo 2/metabolismo , Ratos Wistar , Linfócitos T , Tirosina
11.
PLoS One ; 17(12): e0278965, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36512575

RESUMO

Abnormally high serum homocysteine levels have been associated with several disorders, including obesity, cardiovascular diseases or neurological diseases. Leptin is an anti-obesity protein and its action is mainly mediated by the activation of its Ob-R receptor in neuronal cells. The inability of leptin to induce activation of its specific signaling pathways, especially under endoplasmic reticulum stress, leads to the leptin resistance observed in obesity. The present study examined the effect of homocysteine on leptin signaling in SH-SY5Y neuroblastoma cells expressing the leptin receptor Ob-Rb. Phosphorylation of the signal transducer and activator of transcription (STAT3) and leptin-induced STAT3 transcriptional activity were significantly inhibited by homocysteine treatment. These effects may be specific to homocysteine and to the leptin pathway, as other homocysteine-related compounds, namely methionine and cysteine, have weak effect on leptin-induced inhibition of STAT3 phosphorylation, and homocysteine has no impact on IL-6-induced activation of STAT3. The direct effect of homocysteine on leptin-induced Ob-R activation, analyzed by Ob-R BRET biosensor to monitor Ob-R oligomerization and conformational change, suggested that homocysteine treatment does not affect early events of leptin-induced Ob-R activation. Instead, we found that, unlike methionine or cysteine, homocysteine increases the expression of the endoplasmic reticulum (ER) stress response gene, a homocysteine-sensitive ER resident protein. These results suggest that homocysteine may induce neuronal resistance to leptin by suppressing STAT3 phosphorylation downstream of the leptin receptor via ER stress.


Assuntos
Leptina , Neuroblastoma , Humanos , Leptina/metabolismo , Receptores para Leptina/genética , Homocisteína/farmacologia , Cisteína/farmacologia , Estresse do Retículo Endoplasmático , Fator de Transcrição STAT3/metabolismo , Obesidade/metabolismo , Metionina/farmacologia
12.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 38(12): 1118-1124, 2022 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-36585235

RESUMO

Objective To observe the impact of leptin on the activation of group 2 innate lymphocytes (ILC2) in obese adult patients with allergic rhinitis (AR), and investigate its role and significance in the pathogenesis of AR. Methods A total of 70 patients with AR were enrolled in the study and divided into obese AR group and non-obese AR group according to body mass index (BMI), and matched with 30 cases in the healthy control group with no difference in age and gender during the same period. Flow cytometry was used to detect the ratio of ILC2 in peripheral blood mononuclear cells (PBMCs) of each group, real-time quantitative PCR to detect the expression of leptin mRNA, and ELISA to detect the serum leptin. The correlation between leptin and ILC2 was analyzed, and the changes in the ratio of ILC2 and relevant immune indexes in PBMCs of the AR group before and after the intervention of recombinant leptin were observed. Results Compared with healthy control group, the expressions of leptin and ILC2 of the AR group increased significantly, and the level of the obese AR group was significantly higher than that of the non-obese AR group. The expressions of leptin and ILC2 in the obese AR group were positively correlated in a significant manner. After the intervention of recombinant leptin, the ILC2 level of the obese AR group increased significantly. Conclusion The pathogenesis of AR in obese adults is related to its high expression of leptin, and the activation of ILC2 mediated by leptin aggravates its pathogenetic process.


Assuntos
Leptina , Rinite Alérgica , Humanos , Adulto , Leptina/metabolismo , Linfócitos , Leucócitos Mononucleares/metabolismo , Imunidade Inata , Rinite Alérgica/metabolismo , Obesidade/metabolismo
13.
Mol Med ; 28(1): 159, 2022 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-36539694

RESUMO

BACKGROUND: This study aims to explore the protective role of ethanol extract from Chimonanthus nitens Oliv. leaf (COE) in hyperlipidemia via the leptin/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway. METHODS: Male Sprague‒Dawley rats were randomly divided into 6 groups (n = 8): normal-fat diet (NMD), high-fat diet (HFD), HFD treated with simvastatin (SIM, 5 mg/kg/day), and HFD treated with COE (40, 80, 160 mg/kg/day). Lipid parameters, oxidative stress factors, serum leptin, body weight, hepatic wet weight and liver index were measured. Proteins in the leptin/JAK2/STAT3 pathway in liver tissues were determined using western blotting. Additionally, the expression levels of cytochrome P450 family 7 subfamily A member 1 (CYP7A1) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) were quantified using western blotting and quantitative real-time polymerase chain reaction (qPCR). RESULTS: COE decreased HFD-induced increases in body weight, hepatic wet weight and the liver index. HFD-induced hyperlipidemia and oxidative stress were observed in rat serum and livers. Additionally, COE repressed these two symptoms in rats fed a HFD. Moreover, COE caused CYP7A1 upregulation and HMGCR downregulation in HFD-fed rats. Mechanistically, COE induced the expression of leptin receptor (OB-Rb) and JAK2 and STAT3 phosphorylation in HFD-treated rats. CONCLUSION: COE activates the leptin/JAK2/STAT3 pathway, leading to an improvement in liver function and lipid metabolism and ultimately alleviating hyperlipidemia in rats. Therefore, COE may be a potential hypolipidemic drug for the treatment of hyperlipidemia.


Assuntos
Hiperlipidemias , Leptina , Ratos , Masculino , Animais , Leptina/metabolismo , Leptina/farmacologia , Leptina/uso terapêutico , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Etanol/metabolismo , Etanol/farmacologia , Etanol/uso terapêutico , Ratos Sprague-Dawley , Fator de Transcrição STAT3/metabolismo , Janus Quinase 2/metabolismo , Fígado/metabolismo , Dieta Hiperlipídica/efeitos adversos , Folhas de Planta/metabolismo , Peso Corporal
14.
Biomolecules ; 12(12)2022 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-36551211

RESUMO

Leptin is an adipokine directly correlated with the proinflammatory obese-associated phenotype. Leptin has been demonstrated to inhibit adipogenesis, promote fat demarcation, promote a chronic inflammatory state, increase insulin sensitivity, and promote angiogenesis. Leptin, a regulator of the immune response, is implicated in the pathology of asthma. Studies involved in the key cell reaction and animal models of asthma have provided vital insights into the proinflammatory role of leptin in asthma. Many studies described the immune cell and related cellular pathways activated by leptin, which are beneficial in asthma development and increasing exacerbations. Subsequent studies relating to animal models support the role of leptin in increasing inflammatory cell infiltration, airway hyperresponsiveness, and inflammatory responses. However, the conclusive effects of leptin in asthma are not well elaborated. In the present study, we explored the general functions and the clinical cohort study supporting the association between leptin and asthma. The main objective of our review is to address the knowns and unknowns of leptin on asthma. In this perspective, the arguments about the different faces of leptin in asthma are provided to picture the potential directions, thus yielding a better understanding of asthma development.


Assuntos
Asma , Leptina , Animais , Leptina/metabolismo , Estudos de Coortes , Obesidade/metabolismo , Adipocinas/metabolismo
15.
Int J Mol Sci ; 23(24)2022 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-36555171

RESUMO

Obesity, which is considered a pandemic due to its high prevalence, is a risk factor for many types of cancers, including lymphoma, through a variety of mechanisms by promoting an inflammatory state. Specifically, over the last few decades, obesity has been suggested not only to increase the risk of lymphoma but also to be associated with poor clinical outcomes and worse responses to different treatments for those diseases. Within the extensive range of proinflammatory mediators that adipose tissue releases, leptin has been demonstrated to be a key adipokine due to its pleotropic effects in many physiological systems and diseases. In this sense, different studies have analyzed leptin levels and leptin/leptin receptor expressions as a probable bridge between obesity and lymphomas. Since both obesity and lymphomas are prevalent pathophysiological conditions worldwide and their incidences have increased over the last few years, here we review the possible role of leptin as a promising proinflammatory mediator promoting lymphomas.


Assuntos
Leptina , Linfoma , Humanos , Leptina/metabolismo , Obesidade/complicações , Obesidade/metabolismo , Tecido Adiposo/metabolismo , Adipocinas/metabolismo , Linfoma/metabolismo , Receptores para Leptina/metabolismo
16.
Endocrinology ; 164(2)2022 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-36503981

RESUMO

Timing of puberty requires exquisite coordination of genes, hormones, and brain circuitry. An increasing level of body adiposity, signaled to the brain via the fat-derived hormone leptin, is recognized as a major factor controlling puberty onset. However, it is clear that leptin is not the only metabolic cue regulating puberty, and that developmental regulation of this process also involves tissues other than adipose, with muscle development potentially playing a role in the timing of puberty. The proteolytic processing of fibronectin type 3 domain-containing protein 5 (FNDC5) releases a hormone, irisin. Irisin is primarily produced by muscle and is released into circulation, where levels increase dramatically as puberty approaches. We investigated the effects of a global deletion of the Fndc5 gene on pubertal timing. The absence of irisin induced a delay in puberty onset in female knockout mice compared with controls, without affecting body weight or gonadotropin-releasing hormone (GnRH) neuronal density. We next treated pre-pubertal wild-type male and female mice with an irisin receptor antagonist, cilengitide, for 7 days and observed a delay in first estrus occurrence compared to vehicle-treated control mice. Male puberty timing was unaffected. Next, we deleted the irisin receptor (integrin subunit alpha V) in all forebrain neurons and found a delay in the occurrence of first estrus in knockout females compared to controls. Taken together, these data suggest irisin plays a role in the timing of puberty onset in female mice via a centrally mediated mechanism.


Assuntos
Fibronectinas , Leptina , Camundongos , Masculino , Feminino , Animais , Leptina/metabolismo , Fibronectinas/genética , Fibronectinas/metabolismo , Maturidade Sexual/fisiologia , Obesidade/metabolismo , Peso Corporal , Fatores de Transcrição/metabolismo , Músculo Esquelético/metabolismo
17.
Yi Chuan ; 44(10): 950-957, 2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-36384730

RESUMO

Adipose tissue plays an important role in metabolic physiology through energy storage and endocrine functions. Spatial transcriptomics is revealing the complexity of cell types and their interaction in the adipose tissue with regards to development, homeostasis and disease. Emerging evidence suggests the existence of different subtypes of mature adipocytes that may have distinct functions, the markers of which include leptin (LEP), adiponectin (ADIPOQ), perilipin-1/4 (PLIN), and serum amyloid A (SAA), marking different adipocyte subtypes. Currently, Adipoq-Cre is widely used to study adipocyte biology, however, there is no Cre line that specifically targets LEP+ adipocytes. Here, we report the construction and validation of a Lep-Cre mouse line, which has the endogenous Lep gene edited by the CRISPR-Cas9 technology to generate the Lep-peptide 2A (P2A)-Cre fusion gene. P2A induces an auto-hydrolysis of the fusion protein, leading to expression of the Cre recombinase by the Lep gene activity. The activity of Lep-Cre in different depots of adipose tissues and non-adipose tissues was visualized by the immunofluorescence microscopy in the Lep-Cre Rosa26-loxP-Stop-loxP-tdTomato mice. We showed that Lep-Cre marked white/beige adipose depots extensively, followed by brown adipose depots. Leaky activity was observed in varying degrees among peripheral organs but not in the paraventricular nucleus of the hypothalamus. In summary, we have constructed a new adipocyte-targeting Cre mouse line that would be useful to study the development and physiology of LEP+ adipocytes.


Assuntos
Adipócitos , Leptina , Camundongos , Animais , Leptina/genética , Leptina/metabolismo , Adipócitos/metabolismo , Integrases/genética , Integrases/metabolismo , Transgenes
18.
Nat Metab ; 4(11): 1495-1513, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36411386

RESUMO

Food intake and body weight are tightly regulated by neurons within specific brain regions, including the brainstem, where acute activation of dorsal raphe nucleus (DRN) glutamatergic neurons expressing the glutamate transporter Vglut3 (DRNVglut3) drive a robust suppression of food intake and enhance locomotion. Activating Vglut3 neurons in DRN suppresses food intake and increases locomotion, suggesting that modulating the activity of these neurons might alter body weight. Here, we show that DRNVglut3 neurons project to the lateral hypothalamus (LHA), a canonical feeding center that also reduces food intake. Moreover, chronic DRNVglut3 activation reduces weight in both leptin-deficient (ob/ob) and leptin-resistant diet-induced obese (DIO) male mice. Molecular profiling revealed that the orexin 1 receptor (Hcrtr1) is highly enriched in DRN Vglut3 neurons, with limited expression elsewhere in the brain. Finally, an orally bioavailable, highly selective Hcrtr1 antagonist (CVN45502) significantly reduces feeding and body weight in DIO. Hcrtr1 is also co-expressed with Vglut3 in the human DRN, suggesting that there might be a similar effect in human. These results identify a potential therapy for obesity by targeting DRNVglut3 neurons while also establishing a general strategy for developing drugs for central nervous system disorders.


Assuntos
Tronco Encefálico , Leptina , Neurônios , Redução de Peso , Animais , Humanos , Masculino , Camundongos , Tronco Encefálico/metabolismo , Leptina/metabolismo , Camundongos Obesos , Neurônios/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Receptores de Orexina/metabolismo
19.
Nutrients ; 14(21)2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36364860

RESUMO

BACKGROUND: Hypoxia is caused by the excessive expansion of the white adipose tissue (AT) and is associated with obesity-related conditions such as insulin resistance, inflammation, and oxidative stress. Docosahexaenoic acid (DHA) is an omega-3 fatty acid reported to have beneficial health effects. However, the effects of DHA in AT against hypoxia-induced immune-metabolic perturbations in adipocytes exposed to low O2 tension are not well known. Consequently, this study aimed to evaluate the impact of DHA on markers of inflammation, metabolism, apoptosis, and oxidative stress in 3T3-L1 cell adipocytes exposed to low O2 tension (1% O2) induced hypoxia. METHODS: The apoptosis and reactive oxygen species (ROS) rates were evaluated. Metabolic parameters such as lactate, FFA, glycerol release, glucose uptake, and ATP content were assessed by a fluorometer. The expression of HIF-1, GLUT1 and the secretion of adipocytokines such as leptin, adiponectin, and pro-inflammatory markers was evaluated. RESULTS: DHA-treated hypoxic cells showed significantly decreased basal free fatty acid release, lactate production, and enhanced glucose consumption. In addition, DHA-treatment of hypoxic cells caused a significant reduction in the apoptosis rate and ROS production with decreased lipid peroxidation. Moreover, DHA-treatment of hypoxic cells caused a decreased secretion of pro-inflammatory markers (IL-6, MCP-1) and leptin and increased adiponectin secretion compared with hypoxic cells. Furthermore, DHA-treatment of hypoxic cells caused significant reductions in the expression of genes related to hypoxia (HIF-1, HIF-2), anaerobic metabolism (GLUT1 and Ldha), ATP production (ANT2), and fat metabolism (FASN and PPARY). CONCLUSION: This study suggests that DHA can exert potential anti-obesity effects by reducing the secretion of inflammatory adipokines, oxidative stress, lipolysis, and apoptosis.


Assuntos
Ácidos Docosa-Hexaenoicos , Leptina , Camundongos , Animais , Células 3T3-L1 , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Docosa-Hexaenoicos/metabolismo , Leptina/metabolismo , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Adiponectina/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Adipócitos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Hipóxia/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Adipocinas/metabolismo , Biomarcadores/metabolismo , Lactatos/metabolismo , Trifosfato de Adenosina/metabolismo
20.
Int J Mol Sci ; 23(21)2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36361728

RESUMO

Tumor extracellular vesicles (EVs), as endocytic vesicles able to transport nucleic acids, proteins, and metabolites in recipient cells, have been recognized fundamental mediators of cell-to-cell communication in breast cancer. The biogenesis and release of EVs are highly regulated processes and both the quantity of EVs and their molecular cargo might reflect the metabolic state of the producing cells. We recently demonstrated that the adipokine leptin, whose circulating levels correlate with adipose tissue expansion, is an inducer of EV release from breast cancer cells. Here, we show a specific proteomic signature of EVs released by MCF-7 breast cancer cells grown in the presence of leptin (Lep-EVs), in attempt to find additional molecular effectors linking obesity to breast cancer biology. An analysis of the proteomic profile of Lep-EVs by LC-MS/MS revealed a significant enrichment in biological processes, molecular functions, and cellular components mainly related to mitochondrial machineries and activity, compared to protein content of EVs from untreated breast cancer cells. Metabolic investigations, carried out to assess the autocrine effects of these vesicles on breast cancer cells, revealed that Lep-EVs were able to increase ATP levels in breast cancer cells. This result is associated with increased mitochondrial respiration evaluated by Seahorse analyzer, supporting the concept that Lep-EVs can modulate MCF-7 breast cancer cell oxidative metabolism. Moreover, taking into account the relevance of tumor immune cell crosstalk in the tumor microenvironment (TME), we analyzed the impact of these vesicles on macrophage polarization, the most abundant immune component in the breast TME. We found that tumor-derived Lep-EVs sustain the polarization of M0 macrophages, derived from the human THP-1 monocytic cells, into M2-like tumor-associated macrophages, in terms of metabolic features, phagocytic activity, and increased expression of CD206-positive population. Overall, our results indicate that leptin by inducing the release of EV-enriched in mitochondrial proteins may control the metabolism of MCF-7 breast cancer cells as well as that of macrophages. Characterization of tumor-derived EV protein cargo in an obesity-associated milieu, such as in the presence of elevated leptin levels, might allow identifying unique features and specific metabolic mechanisms useful to develop novel therapeutic approaches for treatment of breast cancer, especially in obese patients.


Assuntos
Neoplasias da Mama , Vesículas Extracelulares , Humanos , Feminino , Proteômica , Neoplasias da Mama/metabolismo , Leptina/metabolismo , Cromatografia Líquida , Espectrometria de Massas em Tandem , Vesículas Extracelulares/metabolismo , Obesidade/metabolismo , Microambiente Tumoral
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