ABSTRACT
Skeletal muscle has gained recognition as an endocrine organ releasing myokines upon contraction during physical exercise. These myokines exert both local and pleiotropic health benefits, underscoring the crucial role of muscle function in countering obesity and contributing to the overall positive effects of exercise on health. Here, we found that exercise activates muscle p38γ, increasing locomotor activity through the secretion of interleukin-15 (IL-15). IL-15 signals in the motor cortex, stimulating locomotor activity. This activation of muscle p38γ, leading to an increase locomotor activity, plays a crucial role in reducing the risk of diabetes and liver steatosis, unveiling a vital muscle-brain communication pathway with profound clinical implications. The correlation between p38γ activation in human muscle during acute exercise and increased blood IL-15 levels highlights the potential therapeutic relevance of this pathway in treating obesity and metabolic diseases. These findings provide valuable insights into the molecular basis of exercise-induced myokine responses promoting physical activity.
Subject(s)
Exercise , Interleukin-15 , Muscle, Skeletal , Interleukin-15/metabolism , Muscle, Skeletal/metabolism , Humans , Animals , Exercise/physiology , Locomotion , Mice , p38 Mitogen-Activated Protein Kinases/metabolism , Signal Transduction , Male , MAP Kinase Signaling System , Obesity/metabolismABSTRACT
OBJECTIVES: In Western society, high-caloric diets rich in fats and sugars have fueled the obesity epidemic and its related disorders. Disruption of the body-brain communication, crucial for maintaining glucose and energy homeostasis, arises from both obesogenic and genetic factors, leading to metabolic disorders. Here, we investigate the role of hypothalamic tanycyte shuttles between the pituitary portal blood and the third ventricle cerebrospinal fluid in regulating energy balance. METHODS: We inhibited vesicle-associated membrane proteins (VAMP1-3)-mediated release in tanycytes by expressing the botulinum neurotoxin type B light chain (BoNT/B) in a Cre-dependent manner in tanycytes. This was achieved by injecting either TAT-Cre in the third ventricle or an AAV1/2 expressing Cre under the control of the tanycyte-specific promoter iodothyronine deiodinase 2 into the lateral ventricle of adult male mice. RESULTS: In male mice fed a standard diet, targeted expression of BoNT/B in adult tanycytes blocks leptin transport into the mediobasal hypothalamus and results in normal-weight central obesity, including increased food intake, abdominal fat deposition, and elevated leptin levels but no marked change in body weight. Furthermore, BoNT/B expression in adult tanycytes promotes fatty acid storage, leading to glucose intolerance and insulin resistance. Notably, these metabolic disturbances occur despite a compensatory increase in insulin secretion, observed both in response to exogenous glucose boluses in vivo and in isolated pancreatic islets. Intriguingly, these metabolic alterations are associated with impaired spatial memory in BoNT/B-expressing mice. CONCLUSIONS: These findings underscore the central role of tanycytes in brain-periphery communication and highlight their potential implication in the age-related development of type 2 diabetes and cognitive decline. Our tanycytic BoNT/B mouse model provides a robust platform for studying how these conditions progress over time, from prediabetic states to full-blown metabolic and cognitive disorders, and the mechanistic contribution of tanycytes to their development. The recognition of the impact of tanycytic transcytosis on hormone transport opens new avenues for developing targeted therapies that could address both metabolic disorders and their associated cognitive comorbidities, which often emerge or worsen with advancing age.
Subject(s)
Energy Metabolism , Ependymoglial Cells , Glucose , Homeostasis , Animals , Male , Mice , Glucose/metabolism , Ependymoglial Cells/metabolism , Cognition/drug effects , Leptin/metabolism , Mice, Inbred C57BL , Hypothalamus/metabolism , Obesity/metabolismABSTRACT
Olanzapine (OLA) is a highly obesogenic second-generation antipsychotic (SGA). Recently we demonstrated that, contrarily to OLA oral treatment, intraperitoneal (i.p.) administration resulted in weight loss and absence of hepatic steatosis in wild-type (WT) and protein tyrosine phosphatase 1B (PTP1B)-deficient (KO) male mice. This protection relied on two central-peripheral axes connecting hypothalamic AMPK with brown/inguinal white adipose tissue (BAT/iWAT) uncoupling protein-1 (UCP-1) and hypothalamic JNK with hepatic fatty acid synthase (FAS). Herein, we addressed OLA i.p. treatment effects in WT and PTP1B-KO female mice. Contrarily to our previous results in WT females receiving OLA orally, the i.p. treatment did not induce weight gain or hyperphagia. Molecularly, in females OLA failed to diminish hypothalamic phospho-AMPK or elevate BAT UCP-1 and energy expenditure (EE) despite the preservation of iWAT browning. Conversely, OLA i.p. treatment in ovariectomized mice reduced hypothalamic phospho-AMPK, increased BAT/iWAT UCP-1 and EE, and induced weight loss as occurred in males. Pretreatment of hypothalamic neurons with 17ß-estradiol (E2) abolished OLA effects on AMPK. Moreover, neither hypothalamic JNK activation nor hepatic FAS upregulation were found in WT and PTP1B-KO females receiving OLA via i.p. Importantly, this axis was reestablished upon ovariectomy. In this line, E2 prevented OLA-induced phospho-JNK in hypothalamic neurons. These results support the role of estrogens in sex-related dimorphism in OLA treatment. This study evidenced the benefit of OLA i.p. administration in preventing its obesogenic effects in female mice that could offer clinical value.
Subject(s)
Adipose Tissue, Brown , Estrogens , Hypothalamus , Liver , Mice, Knockout , Olanzapine , Protein Tyrosine Phosphatase, Non-Receptor Type 1 , Uncoupling Protein 1 , Animals , Female , Adipose Tissue, Brown/metabolism , Adipose Tissue, Brown/drug effects , Hypothalamus/metabolism , Hypothalamus/drug effects , Mice , Liver/metabolism , Liver/drug effects , Estrogens/metabolism , Estrogens/pharmacology , Olanzapine/pharmacology , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 1/genetics , Uncoupling Protein 1/metabolism , Uncoupling Protein 1/genetics , Male , Energy Metabolism/drug effects , Injections, Intraperitoneal , Adipose Tissue, White/metabolism , Adipose Tissue, White/drug effects , Mice, Inbred C57BL , Estradiol/pharmacology , OvariectomyABSTRACT
As the global obesity rate increases, so does the urgency to find effective anti-obesity drugs. In the search for therapeutic targets, central nervous system (CNS) mechanisms engaged in the regulation of energy expenditure and food intake, such as the opioid and dopamine systems, are crucial. In this study, we examined the effect on body weight of two drugs: bromocriptine (BC), a D2R receptor agonist, and PF-04455242, a selective κ opioid receptor (KOR) antagonist. Using diet-induced obese (DIO) rats, we aimed to ascertain whether the administration of BC and PF-04455242, independently or in combination, could enhance body weight loss. Furthermore, the present work demonstrates that the peripheral coadministration of BC and PF-04455242 enhances the reduction of weight in DIO rats and leads to a decrease in adiposity in a food-intake-independent manner. These effects were based on heightened energy expenditure, particularly through the activation of brown adipose tissue (BAT) thermogenesis. Overall, our findings indicate that the combination of BC and PF-04455242 effectively induces body weight loss through increased energy expenditure by increasing thermogenic activity and highlight the importance of the combined use of drugs to combat obesity.
Subject(s)
Biphenyl Compounds , Narcotic Antagonists , Receptors, Opioid, kappa , Sulfonamides , Rats , Animals , Narcotic Antagonists/pharmacology , Dopamine Agonists/pharmacology , Rodentia , Obesity/drug therapy , Obesity/etiology , Obesity/metabolism , Diet , Energy Metabolism , Weight Loss , Receptors, Dopamine/metabolism , Body Weight , Adipose Tissue, Brown/metabolism , ThermogenesisABSTRACT
Olanzapine (OLA), a widely used second-generation antipsychotic (SGA), causes weight gain and metabolic alterations when administered orally to patients. Recently, we demonstrated that, contrarily to the oral treatment which induces weight gain, OLA administered via intraperitoneal (i.p.) in male mice resulted in body weight loss. This protection was due to an increase in energy expenditure (EE) through a mechanism involving the modulation of hypothalamic AMPK activation by higher OLA levels reaching this brain region compared to those of the oral treatment. Since clinical studies have shown hepatic steatosis upon chronic treatment with OLA, herein we further investigated the role of the hypothalamus-liver interactome upon OLA administration in wild-type (WT) and protein tyrosine phosphatase 1B knockout (PTP1B-KO) mice, a preclinical model protected against metabolic syndrome. WT and PTP1B-KO male mice were fed an OLA-supplemented diet or treated via i.p. Mechanistically, we found that OLA i.p. treatment induces mild oxidative stress and inflammation in the hypothalamus in a JNK1-independent and dependent manner, respectively, without features of cell dead. Hypothalamic JNK activation up-regulated lipogenic gene expression in the liver though the vagus nerve. This effect concurred with an unexpected metabolic rewiring in the liver in which ATP depletion resulted in increased AMPK/ACC phosphorylation. This starvation-like signature prevented steatosis. By contrast, intrahepatic lipid accumulation was observed in WT mice treated orally with OLA; this effect being absent in PTP1B-KO mice. We also demonstrated an additional benefit of PTP1B inhibition against hypothalamic JNK activation, oxidative stress and inflammation induced by chronic OLA i.p. treatment, thereby preventing hepatic lipogenesis. The protection conferred by PTP1B deficiency against hepatic steatosis in the oral OLA treatment or against oxidative stress and neuroinflammation in the i.p. treatment strongly suggests that targeting PTP1B might be also a therapeutic strategy to prevent metabolic comorbidities in patients under OLA treatment in a personalized manner.
Subject(s)
Fatty Liver , Signal Transduction , Male , Animals , Mice , Olanzapine/metabolism , Signal Transduction/physiology , Protein Tyrosine Phosphatase, Non-Receptor Type 1 , AMP-Activated Protein Kinases/metabolism , Liver/metabolism , Fatty Liver/drug therapy , Fatty Liver/genetics , Fatty Liver/prevention & control , Mice, Knockout , Inflammation/metabolism , Fatty Acid Synthases/metabolism , Weight Gain , Hypothalamus/metabolism , Mice, Inbred C57BLABSTRACT
BACKGROUND: Second-generation antipsychotics (SGAs) are a mainstay therapy for schizophrenia. SGA-treated patients present higher risk for weight gain, dyslipidemia and hyperglycemia. Herein, we evaluated the effects of olanzapine (OLA), widely prescribed SGA, in mice focusing on changes in body weight and energy balance. We further explored OLA effects in protein tyrosine phosphatase-1B deficient (PTP1B-KO) mice, a preclinical model of leptin hypersensitivity protected against obesity. METHODS: Wild-type (WT) and PTP1B-KO mice were fed an OLA-supplemented diet (5 mg/kg/day, 7 months) or treated with OLA via intraperitoneal (i.p.) injection or by oral gavage (10 mg/kg/day, 8 weeks). Readouts of the crosstalk between hypothalamus and brown or subcutaneous white adipose tissue (BAT and iWAT, respectively) were assessed. The effects of intrahypothalamic administration of OLA with adenoviruses expressing constitutive active AMPKα1 in mice were also analyzed. RESULTS: Both WT and PTP1B-KO mice receiving OLA-supplemented diet presented hyperphagia, but weight gain was enhanced only in WT mice. Unexpectedly, all mice receiving OLA via i.p. lost weight without changes in food intake, but with increased energy expenditure (EE). In these mice, reduced hypothalamic AMPK phosphorylation concurred with elevations in UCP-1 and temperature in BAT. These effects were also found by intrahypothalamic OLA injection and were abolished by constitutive activation of AMPK in the hypothalamus. Additionally, OLA i.p. treatment was associated with enhanced Tyrosine Hydroxylase (TH)-positive innervation and less sympathetic neuron-associated macrophages in iWAT. Both central and i.p. OLA injections increased UCP-1 and TH in iWAT, an effect also prevented by hypothalamic AMPK activation. By contrast, in mice fed an OLA-supplemented diet, BAT thermogenesis was only enhanced in those lacking PTP1B. Our results shed light for the first time that a threshold of OLA levels reaching the hypothalamus is required to activate the hypothalamus BAT/iWAT axis and, therefore, avoid weight gain. CONCLUSION: Our results have unraveled an unexpected metabolic rewiring controlled by hypothalamic AMPK that avoids weight gain in male mice treated i.p. with OLA by activating BAT thermogenesis and iWAT browning and a potential benefit of PTP1B inhibition against OLA-induced weight gain upon oral treatment.
Subject(s)
AMP-Activated Protein Kinases , Hypothalamus , Male , Mice , Animals , Olanzapine/metabolism , Olanzapine/pharmacology , AMP-Activated Protein Kinases/metabolism , Phosphorylation , Hypothalamus/metabolism , Thermogenesis/physiology , Body Weight , Energy Metabolism , Weight Gain , Adipose Tissue, Brown/metabolismABSTRACT
Early-life determinants are thought to be a major factor in the rapid increase of obesity. However, while maternal nutrition has been extensively studied, the effects of breastfeeding by the infant on the reprogramming of energy balance in childhood and throughout adulthood remain largely unknown. Here we show that delayed weaning in rat pups protects them against diet-induced obesity in adulthood, through enhanced brown adipose tissue thermogenesis and energy expenditure. In-depth metabolic phenotyping in this rat model as well as in transgenic mice reveals that the effects of prolonged suckling are mediated by increased hepatic fibroblast growth factor 21 (FGF21) production and tanycyte-controlled access to the hypothalamus in adulthood. Specifically, FGF21 activates GABA-containing neurons expressing dopamine receptor 2 in the lateral hypothalamic area and zona incerta. Prolonged breastfeeding thus constitutes a protective mechanism against obesity by affecting long-lasting physiological changes in liver-to-hypothalamus communication and hypothalamic metabolic regulation.
Subject(s)
Breast Feeding , Obesity , Animals , Female , Fibroblast Growth Factors , Humans , Hypothalamus/metabolism , Liver/metabolism , Mice , Obesity/metabolism , Obesity/prevention & control , RatsABSTRACT
The modulation of the host's metabolism to protect tissue from damage induces tolerance to infections increasing survival. Here, we examined the role of the thyroid hormones, key metabolic regulators, in the outcome of malaria. Hypothyroidism confers protection to experimental cerebral malaria by a disease tolerance mechanism. Hypothyroid mice display increased survival after infection with Plasmodium berghei ANKA, diminishing intracranial pressure and brain damage, without altering pathogen burden, blood-brain barrier disruption, or immune cell infiltration. This protection is reversed by treatment with a Sirtuin 1 inhibitor, while treatment of euthyroid mice with a Sirtuin 1 activator induces tolerance and reduces intracranial pressure and lethality. This indicates that thyroid hormones and Sirtuin 1 are previously unknown targets for cerebral malaria treatment, a major killer of children in endemic malaria areas.
Subject(s)
Hypothyroidism , Malaria, Cerebral , Sirtuin 1 , Animals , Brain/metabolism , Disease Models, Animal , Hypothyroidism/metabolism , Malaria, Cerebral/drug therapy , Malaria, Cerebral/metabolism , Mice , Mice, Inbred C57BL , Plasmodium berghei , Sirtuin 1/antagonists & inhibitors , Sirtuin 1/metabolismABSTRACT
Altered methionine metabolism is associated with weight gain in obesity. The methionine adenosyltransferase (MAT), catalyzing the first reaction of the methionine cycle, plays an important role regulating lipid metabolism. However, its role in obesity, when a plethora of metabolic diseases occurs, is still unknown. By using antisense oligonucleotides (ASO) and genetic depletion of Mat1a, here, we demonstrate that Mat1a deficiency in diet-induce obese or genetically obese mice prevented and reversed obesity and obesity-associated insulin resistance and hepatosteatosis by increasing energy expenditure in a hepatocyte FGF21 dependent fashion. The increased NRF2-mediated FGF21 secretion induced by targeting Mat1a, mobilized plasma lipids towards the BAT to be catabolized, induced thermogenesis and reduced body weight, inhibiting hepatic de novo lipogenesis. The beneficial effects of Mat1a ASO were abolished following FGF21 depletion in hepatocytes. Thus, targeting Mat1a activates the liver-BAT axis by increasing NRF2-mediated FGF21 secretion, which prevents obesity, insulin resistance and hepatosteatosis.
Subject(s)
Adipose Tissue, Brown , Insulin Resistance , Methionine Adenosyltransferase , Obesity , Oligonucleotides, Antisense , Adipose Tissue, Brown/metabolism , Animals , Energy Metabolism , Liver/metabolism , Methionine Adenosyltransferase/genetics , Methionine Adenosyltransferase/metabolism , Mice , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , Obesity/genetics , Obesity/metabolism , Obesity/prevention & control , Oligonucleotides, Antisense/metabolism , Oligonucleotides, Antisense/pharmacologyABSTRACT
Metabolic health depends on the brain's ability to control food intake and nutrient use versus storage, processes that require peripheral signals such as the adipocyte-derived hormone, leptin, to cross brain barriers and mobilize regulatory circuits. We have previously shown that hypothalamic tanycytes shuttle leptin into the brain to reach target neurons. Here, using multiple complementary models, we show that tanycytes express functional leptin receptor (LepR), respond to leptin by triggering Ca2+ waves and target protein phosphorylation, and that their transcytotic transport of leptin requires the activation of a LepR-EGFR complex by leptin and EGF sequentially. Selective deletion of LepR in tanycytes blocks leptin entry into the brain, inducing not only increased food intake and lipogenesis but also glucose intolerance through attenuated insulin secretion by pancreatic ß-cells, possibly via altered sympathetic nervous tone. Tanycytic LepRb-EGFR-mediated transport of leptin could thus be crucial to the pathophysiology of diabetes in addition to obesity, with therapeutic implications.
Subject(s)
Brain/metabolism , Ependymoglial Cells/metabolism , ErbB Receptors/metabolism , Leptin/metabolism , Lipid Metabolism , Pancreas/metabolism , Receptors, Leptin/metabolism , Diabetes Mellitus/etiology , Diabetes Mellitus/metabolism , Energy Metabolism , Insulin-Secreting Cells/metabolism , PhosphorylationABSTRACT
BACKGROUND AND AIMS: G protein-coupled receptor (GPR) 55 is a putative cannabinoid receptor, and l-α-lysophosphatidylinositol (LPI) is its only known endogenous ligand. Although GPR55 has been linked to energy homeostasis in different organs, its specific role in lipid metabolism in the liver and its contribution to the pathophysiology of nonalcoholic fatty liver disease (NAFLD) remains unknown. APPROACH AND RESULTS: We measured (1) GPR55 expression in the liver of patients with NAFLD compared with individuals without obesity and without liver disease, as well as animal models with steatosis and nonalcoholic steatohepatitis (NASH), and (2) the effects of LPI and genetic disruption of GPR55 in mice, human hepatocytes, and human hepatic stellate cells. Notably, we found that circulating LPI and liver expression of GPR55 were up-regulated in patients with NASH. LPI induced adenosine monophosphate-activated protein kinase activation of acetyl-coenzyme A carboxylase (ACC) and increased lipid content in human hepatocytes and in the liver of treated mice by inducing de novo lipogenesis and decreasing ß-oxidation. The inhibition of GPR55 and ACCα blocked the effects of LPI, and the in vivo knockdown of GPR55 was sufficient to improve liver damage in mice fed a high-fat diet and in mice fed a methionine-choline-deficient diet. Finally, LPI promoted the initiation of hepatic stellate cell activation by stimulating GPR55 and activation of ACC. CONCLUSIONS: The LPI/GPR55 system plays a role in the development of NAFLD and NASH by activating ACC.
Subject(s)
Lysophospholipids/metabolism , Non-alcoholic Fatty Liver Disease/metabolism , Obesity/complications , Receptors, Cannabinoid/metabolism , Acetyl-CoA Carboxylase/antagonists & inhibitors , Acetyl-CoA Carboxylase/metabolism , Adult , Aged , Animals , Biopsy , Cannabinoid Receptor Agonists/pharmacology , Cell Line , Cohort Studies , Diet, High-Fat/adverse effects , Disease Models, Animal , Female , Gene Knockdown Techniques , Hepatic Stellate Cells , Hepatocytes , Humans , Lipogenesis/drug effects , Liver/pathology , Lysophospholipids/blood , Male , Mice , Middle Aged , Non-alcoholic Fatty Liver Disease/blood , Non-alcoholic Fatty Liver Disease/etiology , Non-alcoholic Fatty Liver Disease/pathology , Obesity/blood , Obesity/metabolism , Receptors, Cannabinoid/genetics , Up-RegulationABSTRACT
Liver metabolism follows diurnal fluctuations through the modulation of molecular clock genes. Disruption of this molecular clock can result in metabolic disease but its potential regulation by immune cells remains unexplored. Here, we demonstrated that in steady state, neutrophils infiltrated the mouse liver following a circadian pattern and regulated hepatocyte clock-genes by neutrophil elastase (NE) secretion. NE signals through c-Jun NH2-terminal kinase (JNK) inhibiting fibroblast growth factor 21 (FGF21) and activating Bmal1 expression in the hepatocyte. Interestingly, mice with neutropenia, defective neutrophil infiltration or lacking elastase were protected against steatosis correlating with lower JNK activation, reduced Bmal1 and increased FGF21 expression, together with decreased lipogenesis in the liver. Lastly, using a cohort of human samples we found a direct correlation between JNK activation, NE levels and Bmal1 expression in the liver. This study demonstrates that neutrophils contribute to the maintenance of daily hepatic homeostasis through the regulation of the NE/JNK/Bmal1 axis.
Every day, the body's biological processes work to an internal clock known as the circadian rhythm. This rhythm is controlled by 'clock genes' that are switched on or off by daily physical and environmental cues, such as changes in light levels. These daily rhythms are very finely tuned, and disturbances can lead to serious health problems, such as diabetes or high blood pressure. The ability of the body to cycle through the circadian rhythm each day is heavily influenced by the clock of one key organ: the liver. This organ plays a critical role in converting food and drink into energy. There is evidence that neutrophils white blood cells that protect the body by being the first response to inflammation can influence how the liver performs its role in obese people, by for example, releasing a protein called elastase. Additionally, the levels of neutrophils circulating in the blood change following a daily pattern. Crespo, González-Terán et al. wondered whether neutrophils enter the liver at specific times of the day to control liver's daily rhythm. Crespo, González-Terán et al. revealed that neutrophils visit the liver in a pattern that peaks when it gets light and dips when it gets dark by counting the number of neutrophils in the livers of mice at different times of the day. During these visits, neutrophils secreted elastase, which activated a protein called JNK in the cells of the mice's liver. This subsequently blocked the activity of another protein, FGF21, which led to the activation of the genes that allow cells to make fat molecules for storage. JNK activation also switched on the clock gene, Bmal1, ultimately causing fat to build up in the mice's liver. Crespo, González-Terán et al. also found that, in samples from human livers, the levels of elastase, the activity of JNK, and whether the Bmal1 gene was switched on were tightly linked. This suggests that neutrophils may be controlling the liver's rhythm in humans the same way they do in mice. Overall, this research shows that neutrophils can control and reset the liver's daily rhythm using a precisely co-ordinated series of molecular changes. These insights into the liver's molecular clock suggest that elastase, JNK and BmaI1 may represent new therapeutic targets for drugs or smart medicines to treat metabolic diseases such as diabetes or high blood pressure.
Subject(s)
CLOCK Proteins/metabolism , Gene Expression Regulation/physiology , Hepatocytes/metabolism , Neutrophils/physiology , Animals , CLOCK Proteins/genetics , Cells, Cultured , Circadian Rhythm , Fibroblast Growth Factors/genetics , Fibroblast Growth Factors/metabolism , Humans , Inflammation/metabolism , MAP Kinase Kinase 4/genetics , MAP Kinase Kinase 4/metabolism , Mice , Mice, Transgenic , NeutropeniaABSTRACT
The p38 mitogen-activated kinase (MAPK) family controls cell adaptation to stress stimuli. p38 function has been studied in depth in relation to cardiac development and function. The first isoform demonstrated to play an important role in cardiac development was p38α; however, all p38 family members are now known to collaborate in different aspects of cardiomyocyte differentiation and growth. p38 family members have been proposed to have protective and deleterious actions in the stressed myocardium, with the outcome of their action in part dependent on the model system under study and the identity of the activated p38 family member. Most studies to date have been performed with inhibitors that are not isoform-specific, and, consequently, knowledge remains very limited about how the different p38s control cardiac physiology and respond to cardiac stress. In this review, we summarize the current understanding of the role of the p38 pathway in cardiac physiology and discuss recent advances in the field.
Subject(s)
Arrhythmias, Cardiac/metabolism , Cardiomegaly/metabolism , Heart Failure/metabolism , MAP Kinase Signaling System , Myocardium/metabolism , Reperfusion Injury/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , Animals , Humans , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , MAP Kinase Signaling System/drug effects , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Regeneration/physiology , Reperfusion Injury/drug therapy , Treatment Outcome , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitorsABSTRACT
Metabolic stress causes activation of the cJun NH2-terminal kinase (JNK) signal transduction pathway. It is established that one consequence of JNK activation is the development of insulin resistance and hepatic steatosis through inhibition of the transcription factor PPARα. Indeed, JNK1/2 deficiency in hepatocytes protects against the development of steatosis, suggesting that JNK inhibition represents a possible treatment for this disease. However, the long-term consequences of JNK inhibition have not been evaluated. Here we demonstrate that hepatic JNK controls bile acid production. We found that hepatic JNK deficiency alters cholesterol metabolism and bile acid synthesis, conjugation, and transport, resulting in cholestasis, increased cholangiocyte proliferation, and intrahepatic cholangiocarcinoma. Gene ablation studies confirmed that PPARα mediated these effects of JNK in hepatocytes. This analysis highlights potential consequences of long-term use of JNK inhibitors for the treatment of metabolic syndrome.
Subject(s)
Bile Acids and Salts/metabolism , Cholangiocarcinoma/enzymology , Mitogen-Activated Protein Kinase 8/metabolism , Mitogen-Activated Protein Kinase 9/metabolism , Animals , Cholangiocarcinoma/genetics , Cholangiocarcinoma/metabolism , Cholangiocarcinoma/physiopathology , Homeostasis , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mitogen-Activated Protein Kinase 8/genetics , Mitogen-Activated Protein Kinase 9/genetics , PPAR alpha/genetics , PPAR alpha/metabolismABSTRACT
Linaclotide is a synthetic peptide approved by the FDA for the treatment of constipation-predominant irritable bowel syndrome and chronic constipation. Linaclotide binds and activates the transmembrane receptor guanylate cyclase 2C (Gucy2c). Uroguanylin (UGN) is a 16 amino acid peptide that is mainly secreted by enterochromaffin cells in the duodenum and proximal small intestine. UGN is the endogenous ligand of Gucy2c and decreases body weight in diet-induced obese (DIO) mice via the activation of the thermogenic program in brown adipose tissue. Therefore, we wanted to evaluate whether oral linaclotide could also improve DIO mice metabolic phenotype. In this study, we have demonstrated that DIO mice orally treated with linaclotide exhibited a significant reduction of body weight without modifying food intake. Linaclotide exerts its actions through the central nervous system, and more specifically, via Gucy2c receptors located in the mediobasal hypothalamus, leading to the activation of the sympathetic nervous system to trigger the thermogenic activity of brown fat stimulating energy expenditure. These findings indicate for first time that, in addition to its effects at intestinal level to treat irritable bowel syndrome with constipation and chronic constipation, linaclotide also exerts a beneficial effect in whole body metabolism.
Subject(s)
Adipose Tissue, Brown/drug effects , Body Weight/drug effects , Eating/drug effects , Guanylyl Cyclase C Agonists/pharmacology , Hypothalamus/drug effects , Obesity/drug therapy , Peptides/pharmacology , Receptors, Enterotoxin/drug effects , Thermogenesis/drug effects , Animals , Behavior, Animal/drug effects , Diet, High-Fat , Male , Mice , Mice, Inbred C57BLABSTRACT
Dopamine signaling is a crucial part of the brain reward system and can affect feeding behavior. Dopamine receptors are also expressed in the hypothalamus, which is known to control energy metabolism in peripheral tissues. Here we show that pharmacological or chemogenetic stimulation of dopamine receptor 2 (D2R) expressing cells in the lateral hypothalamic area (LHA) and the zona incerta (ZI) decreases body weight and stimulates brown fat activity in rodents in a feeding-independent manner. LHA/ZI D2R stimulation requires an intact sympathetic nervous system and orexin system to exert its action and involves inhibition of PI3K in the LHA/ZI. We further demonstrate that, as early as 3 months after onset of treatment, patients treated with the D2R agonist cabergoline experience an increase in energy expenditure that persists for one year, leading to total body weight and fat loss through a prolactin-independent mechanism. Our results may provide a mechanistic explanation for how clinically used D2R agonists act in the CNS to regulate energy balance.
Subject(s)
Adipose Tissue, Brown/metabolism , Dopamine/metabolism , Hypothalamus/metabolism , Signal Transduction , Thermogenesis/physiology , Animals , Bromocriptine/administration & dosage , Bromocriptine/pharmacology , Female , Humans , Hypothalamus/drug effects , Injections, Intraventricular , Male , RatsABSTRACT
Melanin-concentrating hormone (MCH) is an important regulator of food intake, glucose metabolism, and adiposity. However, the mechanisms mediating these actions remain largely unknown. We used pharmacological and genetic approaches to show that the sirtuin 1 (SIRT1)/FoxO1 signaling pathway in the hypothalamic arcuate nucleus (ARC) mediates MCH-induced feeding, adiposity, and glucose intolerance. MCH reduces proopiomelanocortin (POMC) neuronal activity, and the SIRT1/FoxO1 pathway regulates the inhibitory effect of MCH on POMC expression. Remarkably, the metabolic actions of MCH are compromised in mice lacking SIRT1 specifically in POMC neurons. Of note, the actions of MCH are independent of agouti-related peptide (AgRP) neurons because inhibition of γ-aminobutyric acid receptor in the ARC did not prevent the orexigenic action of MCH, and the hypophagic effect of MCH silencing was maintained after chemogenetic stimulation of AgRP neurons. Central SIRT1 is required for MCH-induced weight gain through its actions on the sympathetic nervous system. The central MCH knockdown causes hypophagia and weight loss in diet-induced obese wild-type mice; however, these effects were abolished in mice overexpressing SIRT1 fed a high-fat diet. These data reveal the neuronal basis for the effects of MCH on food intake, body weight, and glucose metabolism and highlight the relevance of SIRT1/FoxO1 pathway in obesity.
Subject(s)
Adiposity/drug effects , Forkhead Box Protein O1/metabolism , Glucose Intolerance/metabolism , Hyperphagia/metabolism , Hypothalamic Hormones/pharmacology , Melanins/pharmacology , Neurons/drug effects , Pituitary Hormones/pharmacology , Pro-Opiomelanocortin/metabolism , Sirtuin 1/metabolism , Adiposity/physiology , Animals , Forkhead Box Protein O1/genetics , Glucose Intolerance/genetics , Hyperphagia/genetics , Hypothalamus/drug effects , Hypothalamus/metabolism , Male , Mice , Mice, Knockout , Neurons/metabolism , Patch-Clamp Techniques , Rats, Sprague-Dawley , Sirtuin 1/geneticsABSTRACT
Increased body weight is a major factor that interferes with smoking cessation. Nicotine, the main bioactive compound in tobacco, has been demonstrated to have an impact on energy balance, since it affects both feeding and energy expenditure at the central level. Among the central actions of nicotine on body weight, much attention has been focused on its effect on brown adipose tissue (BAT) thermogenesis, though its effect on browning of white adipose tissue (WAT) is unclear. Here, we show that nicotine induces the browning of WAT through a central mechanism and that this effect is dependent on the κ opioid receptor (KOR), specifically in the lateral hypothalamic area (LHA). Consistent with these findings, smokers show higher levels of uncoupling protein 1 (UCP1) expression in WAT, which correlates with smoking status. These data demonstrate that central nicotine-induced modulation of WAT browning may be a target against human obesity.
Subject(s)
Adipose Tissue, Brown/drug effects , Hypothalamus/drug effects , Nicotine/pharmacology , Receptors, Opioid, kappa/metabolism , Thermogenesis/drug effects , Adipose Tissue, Brown/metabolism , Adipose Tissue, White/drug effects , Adipose Tissue, White/metabolism , Adult , Animals , Body Weight/drug effects , Female , Ganglionic Stimulants/administration & dosage , Ganglionic Stimulants/pharmacology , Humans , Hypothalamus/metabolism , Male , Mice, Knockout , Middle Aged , Nicotine/administration & dosage , Rats, Sprague-Dawley , Receptors, Opioid, kappa/genetics , Uncoupling Protein 1/metabolismABSTRACT
Angiopoietin-like protein 4 (ANGPTL-4) regulates lipidic metabolism and affects energy homeostasis. However, its function in children with obesity remains unknown. We investigated plasma ANGPTL-4 levels in children and its relationship with body mass index (BMI) and different lipidic parameters such as free fatty acids (FFA). Plasma ANGPTL-4 levels were analyzed in two different cohorts. In the first cohort (n = 150, age 3-17 years), which included children with normal weight or obesity, we performed a cross-sectional study. In the second cohort, which included only children with obesity (n = 20, age 5-18 years) followed up for two years after an intervention for weight loss, in which we performed a longitudinal study measuring ANGPTL-4 before and after BMI-loss. In the cross-sectional study, circulating ANGPTL-4 levels were lower in children with obesity than in those with normal weight. Moreover, ANGPTL-4 presented a negative correlation with BMI, waist circumference, weight, insulin, homeostasis model assessment of insulin resistance index (HOMA index), triglycerides, and leptin, and a positive correlation with FFA and vitamin-D. In the longitudinal study, the percent change in plasma ANGPTL-4 was correlated with the percent change in FFA, total-cholesterol and high-density lipoprotein cholesterol. This study reveals a significant association of ANGPTL-4 with pediatric obesity and plasma lipid profile.
Subject(s)
Angiopoietin-Like Protein 4/blood , Lipids/blood , Obesity/blood , Obesity/epidemiology , Adolescent , Body Mass Index , Child , Child, Preschool , Cross-Sectional Studies , Humans , Ideal Body Weight/physiology , Longitudinal StudiesABSTRACT
The gastrointestinal-brain axis is a key mediator of the body weight and energy homeostasis regulation. Uroguanylin (UGN) has been recently proposed to be a part of this gut-brain axis regulating food intake, body weight and energy expenditure. Expression of UGN is regulated by the nutritional status and dependent on leptin levels. However, the exact molecular mechanisms underlying this UGN-leptin metabolic regulation at a hypothalamic level still remains unclear. Using leptin resistant diet-induced obese (DIO) mice, we aimed to determine whether UGN could improve hypothalamic leptin sensitivity. The present work demonstrates that the central co-administration of UGN and leptin potentiates leptin's ability to decrease the food intake and body weight in DIO mice, and that UGN activates the hypothalamic signal transducer and activator of transcription 3 (STAT3) and phosphatidylinositide 3-kinases (PI3K) pathways. At a functional level, the blockade of PI3K, but not STAT3, blunted UGN-mediated leptin responsiveness in DIO mice. Overall, these findings indicate that UGN improves leptin sensitivity in DIO mice.