RESUMEN
PAQR4 is an orphan receptor in the PAQR family with an unknown function in metabolism. Here, we identify a critical role of PAQR4 in maintaining adipose tissue function and whole-body metabolic health. We demonstrate that expression of Paqr4 specifically in adipocytes, in an inducible and reversible fashion, leads to partial lipodystrophy, hyperglycaemia and hyperinsulinaemia, which is ameliorated by wild-type adipose tissue transplants or leptin treatment. By contrast, deletion of Paqr4 in adipocytes improves healthy adipose remodelling and glucose homoeostasis in diet-induced obesity. Mechanistically, PAQR4 regulates ceramide levels by mediating the stability of ceramide synthases (CERS2 and CERS5) and, thus, their activities. Overactivation of the PQAR4-CERS axis causes ceramide accumulation and impairs adipose tissue function through suppressing adipogenesis and triggering adipocyte de-differentiation. Blocking de novo ceramide biosynthesis rescues PAQR4-induced metabolic defects. Collectively, our findings suggest a critical function of PAQR4 in regulating cellular ceramide homoeostasis and targeting PAQR4 offers an approach for the treatment of metabolic disorders.
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Adipocitos , Ceramidas , Ceramidas/metabolismo , Adipocitos/metabolismo , Animales , Ratones , Adipogénesis , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Tejido Adiposo/metabolismo , Obesidad/metabolismo , HumanosRESUMEN
For more than a century, physicians have searched for ways to pharmacologically reduce excess body fat. The tide has finally turned with recent advances in biochemically engineered agonists for the receptor of glucagon-like peptide-1 (GLP-1) and their use in GLP-1-based polyagonists. These polyagonists reduce body weight through complementary pharmacology by incorporating the receptors for glucagon and/or the glucose-dependent insulinotropic polypeptide (GIP). In their most advanced forms, gut-hormone polyagonists achieve an unprecedented weight reduction of up to â¼20%-30%, offering a pharmacological alternative to bariatric surgery. Along with favorable effects on glycemia, fatty liver, and kidney disease, they also offer beneficial effects on the cardiovascular system and adipose tissue. These new interventions, therefore, hold great promise for the future of anti-obesity medications.
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Fármacos Antiobesidad , Obesidad , Humanos , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Fármacos Antiobesidad/uso terapéutico , Fármacos Antiobesidad/farmacología , Animales , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Tejido Adiposo/metabolismo , Tejido Adiposo/efectos de los fármacosRESUMEN
Recent studies have found that glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism can enhance the metabolic efficacy of glucagon-like peptide-1 receptor agonist treatment by promoting both weight-dependent and -independent improvements on systemic insulin sensitivity. These findings have prompted new investigations aimed at better understanding the broad metabolic benefit of GIPR activation. Herein, we determined whether GIPR agonism favorably influenced the pharmacologic efficacy of the insulin-sensitizing thiazolidinedione (TZD) rosiglitazone in obese insulin-resistant (IR) mice. Genetic and pharmacological approaches were used to examine the role of GIPR signaling on rosiglitazone-induced weight gain, hyperphagia, and glycemic control. RNA sequencing was conducted to uncover potential mechanisms by which GIPR activation influences energy balance and insulin sensitivity. In line with previous findings, treatment with rosiglitazone induced the mRNA expression of the GIPR in white and brown fat. However, obese GIPR-null mice dosed with rosiglitazone had equivalent weight gain to that of wild-type (WT) animals. Strikingly, chronic treatment of obese IR WT animals with a long-acting GIPR agonist prevented rosiglitazone-induced weight-gain and hyperphagia, and it enhanced the insulin-sensitivity effect of this TZD. The systemic insulin sensitization was accompanied by increased glucose disposal in brown adipose tissue, which was underlined by the recruitment of metabolic and thermogenic genes. These findings suggest that GIPR agonism can counter the negative consequences of rosiglitazone treatment on body weight and adiposity, while improving its insulin-sensitizing efficacy at the same time.
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Resistencia a la Insulina , Receptores de la Hormona Gastrointestinal , Tiazolidinedionas , Ratones , Animales , Insulina/metabolismo , Resistencia a la Insulina/fisiología , Rosiglitazona/uso terapéutico , Obesidad/metabolismo , Tiazolidinedionas/uso terapéutico , Receptores de la Hormona Gastrointestinal/metabolismo , Aumento de Peso , Insulina Regular Humana/uso terapéutico , Hiperfagia , Polipéptido Inhibidor Gástrico/farmacologíaRESUMEN
Partial leptin reduction can induce significant weight loss, while weight loss contributes to partial leptin reduction. The cause-and-effect relationship between leptin reduction and weight loss remains to be further elucidated. Here, we show that FGF21 and the glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide rapidly induced a reduction in leptin. This leptin reduction contributed to the beneficial effects of GLP-1R agonism in metabolic health, as transgenically maintaining leptin levels during treatment partially curtailed the beneficial effects seen with these agonists. Moreover, a higher degree of leptin reduction during treatment, induced by including a leptin neutralizing antibody with either FGF21 or liraglutide, synergistically induced greater weight loss and better glucose tolerance in diet-induced obese mice. Furthermore, upon cessation of either liraglutide or FGF21 treatment, the expected immediate weight regain was observed, associated with a rapid increase in circulating leptin levels. Prevention of this leptin surge with leptin neutralizing antibodies slowed down weight gain and preserved better glucose tolerance. Mechanistically, a significant reduction in leptin induced a higher degree of leptin sensitivity in hypothalamic neurons. Our observations support a model that postulates that a reduction of leptin levels is a necessary prerequisite for substantial weight loss, and partial leptin reduction is a viable strategy to treat obesity and its associated insulin resistance.
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Leptina , Liraglutida , Animales , Ratones , Leptina/metabolismo , Liraglutida/farmacología , Obesidad , Pérdida de Peso , Glucosa/metabolismo , Receptor del Péptido 1 Similar al Glucagón/metabolismoRESUMEN
Despite their high degree of effectiveness in the management of psychiatric conditions, exposure to antipsychotic drugs, including olanzapine and risperidone, is frequently associated with substantial weight gain and the development of diabetes. Even before weight gain, a rapid rise in circulating leptin concentrations can be observed in most patients taking antipsychotic drugs. To date, the contribution of this hyperleptinemia to weight gain and metabolic deterioration has not been defined. Here, with an established mouse model that recapitulates antipsychotic drug-induced obesity and insulin resistance, we not only confirm that hyperleptinemia occurs before weight gain but also demonstrate that hyperleptinemia contributes directly to the development of obesity and associated metabolic disorders. By suppressing the rise in leptin through the use of a monoclonal leptin-neutralizing antibody, we effectively prevented weight gain, restored glucose tolerance, and preserved adipose tissue and liver function in antipsychotic drug-treated mice. Mechanistically, suppressing excess leptin resolved local tissue and systemic inflammation typically associated with antipsychotic drug treatment. We conclude that hyperleptinemia is a key contributor to antipsychotic drug-associated weight gain and metabolic deterioration. Leptin suppression may be an effective approach to reducing the undesirable side effects of antipsychotic drugs.
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Antipsicóticos , Enfermedades Metabólicas , Humanos , Ratones , Animales , Antipsicóticos/efectos adversos , Leptina/metabolismo , Obesidad/metabolismo , Aumento de PesoRESUMEN
Adiponectin is a secretory protein, primarily produced in adipocytes. However, low but detectable expression of adiponectin can be observed in cell types beyond adipocytes, particularly in kidney tubular cells, but its local renal role is unknown. We assessed the impact of renal adiponectin by utilizing male inducible kidney tubular cell-specific adiponectin overexpression or knockout mice. Kidney-specific adiponectin overexpression induces a doubling of phosphoenolpyruvate carboxylase expression and enhanced pyruvate-mediated glucose production, tricarboxylic acid cycle intermediates and an upregulation of fatty acid oxidation (FAO). Inhibition of FAO reduces the adiponectin-induced enhancement of glucose production, highlighting the role of FAO in the induction of renal gluconeogenesis. In contrast, mice lacking adiponectin in the kidney exhibit enhanced glucose tolerance, lower utilization and greater accumulation of lipid species. Hence, renal adiponectin is an inducer of gluconeogenesis by driving enhanced local FAO and further underlines the important systemic contribution of renal gluconeogenesis.
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Adiponectina , Gluconeogénesis , Riñón , Animales , Masculino , Ratones , Adiponectina/genética , Adiponectina/metabolismo , Gluconeogénesis/genética , Gluconeogénesis/fisiología , Glucosa/metabolismo , Riñón/metabolismo , Hígado/metabolismo , Ratones Noqueados , Ácido Pirúvico/metabolismoRESUMEN
The disease progression of the metabolic syndrome is associated with prolonged hyperlipidemia and insulin resistance, eventually giving rise to impaired insulin secretion, often concomitant with hypoadiponectinemia. As an adipose tissue derived hormone, adiponectin is beneficial for insulin secretion and ß cell health and differentiation. However, the down-stream pathway of adiponectin in the pancreatic islets has not been studied extensively. Here, along with the overall reduction of endocrine pancreatic function in islets from adiponectin KO mice, we examine PPARα and HNF4α as additional down-regulated transcription factors during a prolonged metabolic challenge. To elucidate the function of ß cell-specific PPARα and HNF4α expression, we developed doxycycline inducible pancreatic ß cell-specific PPARα (ß-PPARα) and HNF4α (ß-HNF4α) overexpression mice. ß-PPARα mice exhibited improved protection from lipotoxicity, but elevated ß-oxidative damage in the islets, and also displayed lowered phospholipid levels and impaired glucose-stimulated insulin secretion. ß-HNF4α mice showed a more severe phenotype when compared to ß-PPARα mice, characterized by lower body weight, small islet mass and impaired insulin secretion. RNA-sequencing of the islets of these models highlights overlapping yet unique roles of ß-PPARα and ß-HNF4α. Given that ß-HNF4α potently induces PPARα expression, we define a novel adiponectin-HNF4α-PPARα cascade. We further analyzed downstream genes consistently regulated by this axis. Among them, the islet amyloid polypeptide (IAPP) gene is an important target and accumulates in adiponectin KO mice. We propose a new mechanism of IAPP aggregation in type 2 diabetes through reduced adiponectin action.
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Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Animales , Ratones , Adiponectina/genética , Adiponectina/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismoRESUMEN
OBJECTIVE: Renal fibrosis is a hallmark for chronic kidney disease (CKD), and often leads to end stage renal disease (ESRD). However, limited interventions are available clinically to ameliorate or reverse renal fibrosis. METHODS: Herein, we evaluated whether blockade of endotrophin through neutralizing antibodies protects from renal fibrosis in the podocyte insult model (the "POD-ATTAC" mouse). We determined the therapeutic effects of endotrophin targeted antibody through assessing renal function, renal inflammation and fibrosis at histological and transcriptional levels, and podocyte regeneration. RESULTS: We demonstrated that neutralizing endotrophin antibody treatment significantly ameliorates renal fibrosis at the transcriptional, morphological, and functional levels. In the antibody treatment group, expression of pro-inflammatory and pro-fibrotic genes was significantly reduced, normal renal structures were restored, collagen deposition was decreased, and proteinuria and renal function were improved. We further performed a lineage tracing study confirming that podocytes regenerate as de novo podocytes upon injury and loss, and blockade of endotrophin efficiently enhances podocyte-specific marker expressions. CONCLUSION: Combined, we provide pre-clinical evidence supporting neutralizing endotrophin as a promising therapy for intervening with renal fibrosis in CKD, and potentially in other chronic fibro-inflammatory diseases.
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Podocitos , Insuficiencia Renal Crónica , Ratones , Animales , Podocitos/patología , Fragmentos de Péptidos/metabolismo , Fibrosis , Insuficiencia Renal Crónica/metabolismo , Anticuerpos/metabolismoRESUMEN
Iron is essential to many fundamental biological processes, but its cellular compartmentalization and concentration must be tightly controlled. Although iron overload can contribute to obesity-associated metabolic deterioration, the subcellular localization and accumulation of iron in adipose tissue macrophages is largely unknown. Here, we show that macrophage mitochondrial iron levels control systemic metabolism in male mice by altering adipocyte iron concentrations. Using various transgenic mouse models to manipulate the macrophage mitochondrial matrix iron content in an inducible fashion, we demonstrate that lowering macrophage mitochondrial matrix iron increases numbers of M2-like macrophages in adipose tissue, lowers iron levels in adipocytes, attenuates inflammation and protects from high-fat-diet-induced metabolic deterioration. Conversely, elevating macrophage mitochondrial matrix iron increases M1-like macrophages and iron levels in adipocytes, exacerbates inflammation and worsens high-fat-diet-induced metabolic dysfunction. These phenotypes are robustly reproduced by transplantation of a small amount of fat from transgenic to wild-type mice. Taken together, we identify macrophage mitochondrial iron levels as a crucial determinant of systemic metabolic homeostasis in mice.
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Tejido Adiposo , Hierro , Masculino , Ratones , Animales , Hierro/metabolismo , Tejido Adiposo/metabolismo , Macrófagos/metabolismo , Adipocitos/metabolismo , Inflamación/metabolismoRESUMEN
Obesity is associated with increased cancer incidence and progression. However, the relationship between adiposity and cancer remains poorly understood at the mechanistic level. Here, we report that adipocytes from tumor-invasive mammary fat undergo de-differentiation to fibroblast-like precursor cells during tumor progression and integrate into the tumor microenvironment. Single-cell sequencing reveals that these de-differentiated adipocytes lose their original identities and transform into multiple cell types, including myofibroblast- and macrophage-like cells, with their characteristic features involved in immune response, inflammation, and extracellular matrix remodeling. The de-differentiated cells are metabolically distinct from tumor-associated fibroblasts but exhibit comparable effects on tumor cell proliferation. Inducing de-differentiation by Xbp1s overexpression promotes tumor progression despite lower adiposity. In contrast, promoting lipid-storage capacity in adipocytes through MitoNEET overexpression curbs tumor growth despite greater adiposity. Collectively, the metabolic interplay between tumor cells and adipocytes induces adipocyte mesenchymal transition and contributes to reconfigure the stroma into a more tumor-friendly microenvironment.
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Neoplasias de la Mama , Neoplasias Mamarias Animales , Adipocitos/metabolismo , Animales , Neoplasias de la Mama/patología , Matriz Extracelular/metabolismo , Femenino , Humanos , Neoplasias Mamarias Animales/patología , Microambiente TumoralRESUMEN
Adipocytes undergo intense energetic stress in obesity resulting in loss of mitochondrial mass and function. We have found that adipocytes respond to mitochondrial stress by rapidly and robustly releasing small extracellular vesicles (sEVs). These sEVs contain respiration-competent, but oxidatively damaged mitochondrial particles, which enter circulation and are taken up by cardiomyocytes, where they trigger a burst of ROS. The result is compensatory antioxidant signaling in the heart that protects cardiomyocytes from acute oxidative stress, consistent with a preconditioning paradigm. As such, a single injection of sEVs from energetically stressed adipocytes limits cardiac ischemia/reperfusion injury in mice. This study provides the first description of functional mitochondrial transfer between tissues and the first vertebrate example of "inter-organ mitohormesis." Thus, these seemingly toxic adipocyte sEVs may provide a physiological avenue of potent cardio-protection against the inevitable lipotoxic or ischemic stresses elicited by obesity.
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Adipocitos , Vesículas Extracelulares , Adipocitos/metabolismo , Animales , Vesículas Extracelulares/metabolismo , Ratones , Mitocondrias/metabolismo , Mitocondrias Cardíacas , Miocitos Cardíacos/metabolismo , Estrés OxidativoRESUMEN
Iron overload is positively associated with diabetes risk. However, the role of iron in adipose tissue remains incompletely understood. Here, we report that transferrin-receptor-1-mediated iron uptake is differentially required for distinct subtypes of adipocytes. Notably, adipocyte-specific transferrin receptor 1 deficiency substantially protects mice from high-fat-diet-induced metabolic disorders. Mechanistically, low cellular iron levels have a positive impact on the health of the white adipose tissue and can restrict lipid absorption from the intestine through modulation of vesicular transport in enterocytes following high-fat diet feeding. Specific reduction of adipocyte iron by AAV-mediated overexpression of the iron exporter Ferroportin1 in adult mice effectively mimics these protective effects. In summary, our studies highlight an important role of adipocyte iron in the maintenance of systemic metabolism through an adipocyte-enterocyte axis, offering an additional level of control over caloric influx into the system after feeding by regulating intestinal lipid absorption.
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Adipocitos , Tejido Adiposo , Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Animales , Dieta Alta en Grasa , Hierro/metabolismo , Lípidos , Ratones , Obesidad/metabolismoRESUMEN
BACKGROUND & AIMS: We have previously reported that the mitochondrial dicarboxylate carrier (mDIC [SLC25A10]) is predominantly expressed in the white adipose tissue (WAT) and subject to regulation by metabolic cues. However, the specific physiological functions of mDIC and the reasons for its abundant presence in adipocytes are poorly understood. METHODS: To systemically investigate the impact of mDIC function in adipocytes in vivo, we generated loss- and gain-of-function mouse models, selectively eliminating or overexpressing mDIC in mature adipocytes, respectively. RESULTS: In in vitro differentiated white adipocytes, mDIC is responsible for succinate transport from the mitochondrial matrix to the cytosol, from where succinate can act on the succinate receptor SUCNR1 and inhibit lipolysis by dampening the cAMP- phosphorylated hormone-sensitive lipase (pHSL) pathway. We eliminated mDIC expression in adipocytes in a doxycycline (dox)-inducible manner (mDICiKO) and demonstrated that such a deletion results in enhanced adipocyte lipolysis and promotes high-fat diet (HFD)-induced adipocyte dysfunction, liver lipotoxicity, and systemic insulin resistance. Conversely, in a mouse model with dox-inducible, adipocyte-specific overexpression of mDIC (mDICiOE), we observed suppression of adipocyte lipolysis both in vivo and ex vivo. mDICiOE mice are potently protected from liver lipotoxicity upon HFD feeding. Furthermore, they show resistance to HFD-induced weight gain and adipose tissue expansion with concomitant improvements in glucose tolerance and insulin sensitivity. Beyond our data in rodents, we found that human WAT SLC25A10 mRNA levels are positively correlated with insulin sensitivity and negatively correlated with intrahepatic triglyceride levels, suggesting a critical role of mDIC in regulating overall metabolic homeostasis in humans as well. CONCLUSIONS: In summary, we highlight that mDIC plays an essential role in governing adipocyte lipolysis and preventing liver lipotoxicity in response to a HFD. LAY SUMMARY: Dysfunctional fat tissue plays an important role in the development of fatty liver disease and liver injury. Our present study identifies a mitochondrial transporter, mDIC, which tightly controls the release of free fatty acids from adipocytes to the liver through the export of succinate from mitochondria. We believe this mDIC-succinate axis could be targeted for the treatment of fatty liver disease.
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Adipocitos/metabolismo , Mitocondrias Hepáticas/patología , Animales , Modelos Animales de Enfermedad , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias Hepáticas/metabolismoRESUMEN
The adipose tissue stroma is a rich source of molecularly distinct stem and progenitor cell populations with diverse functions in metabolic regulation, adipogenesis, and inflammation. The ontology of these populations and the mechanisms that govern their behaviors in response to stimuli, such as overfeeding, however, are unclear. Here, we show that the developmental fates and functional properties of adipose platelet-derived growth factor receptor beta (PDGFRß)+ progenitor subpopulations are tightly regulated by mitochondrial metabolism. Reducing the mitochondrial ß-oxidative capacity of PDGFRß+ cells via inducible expression of MitoNEET drives a pro-inflammatory phenotype in adipose progenitors and alters lineage commitment. Furthermore, disrupting mitochondrial function in PDGFRß+ cells rapidly induces alterations in immune cell composition in lean mice and impacts expansion of adipose tissue in diet-induced obesity. The adverse effects on adipose tissue remodeling can be reversed by restoring mitochondrial activity in progenitors, suggesting therapeutic potential for targeting energy metabolism in these cells.
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Adipogénesis , Tejido Adiposo Blanco , Tejido Adiposo/metabolismo , Tejido Adiposo Blanco/metabolismo , Animales , Proteínas de Unión a Hierro/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , Mitocondrias , Células Madre/metabolismoRESUMEN
The landmark discoveries of leptin and adiponectin firmly established adipose tissue as a sophisticated and highly active endocrine organ, opening a new era of investigating adipose-mediated tissue crosstalk. Both obesity-associated hyperleptinemia and hypoadiponectinemia are important biomarkers to predict cardiovascular outcomes, suggesting a crucial role for adiponectin and leptin in obesity-associated cardiovascular disorders. Normal physiological levels of adiponectin and leptin are indeed essential to maintain proper cardiovascular function. Insufficient adiponectin and leptin signaling results in cardiovascular dysfunction. However, a paradox of high levels of both leptin and adiponectin is emerging in the pathogenesis of cardiovascular disorders. Here, we (1) summarize the recent progress in the field of adiponectin and leptin and its association with cardiovascular disorders, (2) further discuss the underlying mechanisms for this new paradox of leptin and adiponectin action, and (3) explore the possible application of partial leptin reduction, in addition to increasing the adiponectin/leptin ratio as a means to prevent or reverse cardiovascular disorders.
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Adiponectina/metabolismo , Tejido Adiposo/metabolismo , Enfermedades Cardiovasculares/metabolismo , Sistema Cardiovascular/metabolismo , Leptina/metabolismo , Obesidad/metabolismo , Adiponectina/deficiencia , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/patología , Tejido Adiposo/fisiopatología , Animales , Fármacos Antiobesidad/uso terapéutico , Cirugía Bariátrica , Fármacos Cardiovasculares/uso terapéutico , Enfermedades Cardiovasculares/patología , Enfermedades Cardiovasculares/fisiopatología , Enfermedades Cardiovasculares/terapia , Sistema Cardiovascular/efectos de los fármacos , Sistema Cardiovascular/patología , Sistema Cardiovascular/fisiopatología , Humanos , Errores Innatos del Metabolismo/metabolismo , Obesidad/patología , Obesidad/fisiopatología , Obesidad/terapia , Transducción de SeñalRESUMEN
Dermal fibroblasts are an essential population of skin cells. They are not only responsible for synthesis and remodelling of the extracellular matrix of the dermis, but also communicate with other skin cells via autocrine and paracrine interactions. Skin-associated dermal adipocytes reside below the reticular dermis. Strong lipolysis is observed during the regression of dermal adipocytes. However, the nature of the local intercellular crosstalk in which lipids released by dermal adipocytes affecting the metabolism of adjacent skin fibroblasts has not yet been examined. With the use of a series of novel mouse models that allow us to manipulate adipocytes, we demonstrate that dermal adipocytes can modulate the structure of the dermis through regulating extracellular matrix production in dermal fibroblasts. Fatty acids released by dermal adipocytes are involved in this process. Our observations offer new in vivo insights into the role of dermal adipocyte-derived lipids in influencing metabolism of adjacent local cells in the skin through a paracrine effect in the microenvironment of the dermal adipocyte.
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Adipocitos/metabolismo , Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Comunicación Paracrina , Tejido Adiposo Blanco/citología , Tejido Adiposo Blanco/metabolismo , Animales , Microambiente Celular , Colágeno/genética , Colágeno Tipo I/genética , Cadena alfa 1 del Colágeno Tipo I/genética , Colágeno Tipo III/genética , Células del Cúmulo , Dieta Alta en Grasa , Ácidos Grasos/metabolismo , Femenino , Expresión Génica , Lipólisis , Masculino , Ratones , Piel/citologíaRESUMEN
OBJECTIVE: Obesity-induced insulin resistance is closely associated with chronic subclinical inflammation in white adipose tissue. However, the mechanistic involvement of adipocyte-derived inflammation under these disease conditions remains unclear. Our aim was to investigate the relative inflammation-related contributions of adipocytes and macrophages to insulin sensitivity. METHODS: RIDα/ß is an adenoviral protein complex that inhibits several inflammatory pathways, including TLR4, TNFα, and IL1ß signaling. We generated novel mouse models with adipocyte-specific and macrophage-specific doxycycline (dox)-inducible RIDα/ß-transgenic mice (RIDad and RIDmac mice, respectively). RESULTS: RIDα/ß induction significantly reduced LPS-stimulated inflammatory markers, such as Tnf, Il1b, and Saa3 in adipose tissues. Surprisingly, RIDad mice had elevated levels of postprandial glucose and insulin and exhibited glucose intolerance and insulin resistance, even under chow-fed conditions. Moreover, the RIDad mice displayed further insulin resistance under obesogenic (high-fat diet, HFD) conditions despite reduced weight gain. In addition, under pre-existing obese and inflamed conditions on an HFD, subsequent induction of RIDα/ß in RIDad mice reduced body weight gain, further exacerbating glucose tolerance, enhancing insulin resistance and fatty liver, and reducing adiponectin levels. This occurred despite effective suppression of the inflammatory pathways (including TNFα and IL1ß). In contrast, RIDmac mice, upon HFD feeding, displayed similar weight gain, comparable adiponectin levels, and insulin sensitivity, suggesting that the inflammatory properties of macrophages did not exert a negative impact on metabolic readouts. RIDα/ß expression and the ensuing suppression of inflammation in adipocytes enhanced adipose tissue fibrosis and reduced vascularization. CONCLUSION: Our novel findings further corroborate our previous observations suggesting that suppressing adipocyte inflammation impairs adipose tissue function and promotes insulin resistance, despite beneficial effects on weight gain.
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Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Inflamación/metabolismo , Resistencia a la Insulina , Insulina/metabolismo , Animales , Citocinas/metabolismo , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Glucosa/metabolismo , Intolerancia a la Glucosa/metabolismo , Inmunohistoquímica , Inflamación/tratamiento farmacológico , Inflamación/etiología , Inflamación/patología , Mediadores de Inflamación/metabolismo , Macrófagos/metabolismo , Ratones , Ratones Transgénicos , Obesidad/etiología , Obesidad/metabolismo , Obesidad/patologíaRESUMEN
OBJECTIVE: Hyperleptinemia per se is sufficient to promote leptin resistance in the obese state. Leptin sensitivity can be restored by reducing circulating leptin levels within a physiologically healthy range and is a viable antiobesity and antidiabetic strategy. However, a previous study suggests that partial leptin deficiency favors diet-induced obesity and related metabolic disorders in mice, arguing that a lower leptin level may indeed promote diet-induced obesity and its associated metabolic disorders. Here, we aim to elucidate what the impact of partial leptin deficiency is on fat mass and insulin sensitivity. METHODS: We used two different mouse models of partial leptin deficiency: an adipocyte-specific congenital heterozygous leptin knockout mouse line (LepHZ) and the well-established whole body heterozygous leptin knockout mouse (OBHZ). The metabolic studies of OBHZ and LepHZ mice were performed both on normal carbohydrate-rich chow diet and on a high-fat diet (HFD). Male and female mice were included in the study to account for sex-specific differences. Body weight, food intake, glucose tolerance, and insulin tolerance were tested. Histology of adipose tissue and liver tissue allowed insights into adipose tissue inflammation and hepatic triglyceride content. Immunohistochemistry was paired with RT-PCR analysis for expression levels of inflammatory markers. RESULTS: Both OBHZ and LepHZ mice displayed reduced circulating leptin levels on the chow diet and HFD. On chow diet, male OBHZ and LepHZ mice showed elevated fat mass and body weight, while their glucose tolerance and insulin sensitivity remained unchanged. However, the inability in partially leptin-deficient mice to fully induce circulating leptin during the development of diet-induced obesity results in reduced food intake and leaner mice with lower body weight compared to their littermate controls. Importantly, a strong reduction of adipose tissue inflammation is observed along with improvements in insulin sensitivity and enhanced glucose tolerance. Additionally, partial leptin deficiency protects the mice from fatty liver and liver fibrosis. Chronically HFD-fed OBHZ and LepHZ mice remain more sensitive to exogenous leptin injection, as reflected by their reduced food intake upon an acute leptin treatment. CONCLUSION: In response to HFD feeding, the inability to upregulate leptin levels due to partial leptin deficiency protects mice from diet-induced obesity and metabolic dysregulation. Thus, in an obesogenic environment, maintaining lower leptin levels is highly beneficial for both obesity and diabetes management. Chronic leptin reduction represents a viable preventive strategy whose efficacy awaits clinical testing.
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Leptina/deficiencia , Leptina/metabolismo , Obesidad/metabolismo , Tejido Adiposo/metabolismo , Tejido Adiposo Blanco/metabolismo , Animales , Composición Corporal/fisiología , Peso Corporal/fisiología , Dieta Alta en Grasa , Hígado Graso/fisiopatología , Femenino , Insulina/metabolismo , Resistencia a la Insulina/fisiología , Hígado/metabolismo , Hígado/patología , Masculino , Enfermedades Metabólicas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Obesos , Obesidad/prevención & controlRESUMEN
The successful use of leptin for the treatment of individuals with lipodystrophy and leptin deficiency is well established. However, pharmacological approaches of leptin therapy for the treatment of diet-induced obesity have been ineffective. There is ample room for a better understanding of the much famed "leptin resistance" phenomenon. Our recent data in this area prompt us to call for a conceptual shift. This shift entails a model in which a reduction of bioactive leptin levels in the context of obesity triggers a high degree of leptin sensitization and improved leptin action, both centrally and peripherally. Put another way, hyperleptinemia per se causes leptin resistance and associated metabolic disorders. In this perspective, we briefly discuss the underlying conceptual steps that led us to explore partial leptin reduction as a viable therapeutic avenue. We hope this discussion will contribute to potential future applications of partial leptin reduction therapy for the treatment of obesity and type 2 diabetes.
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Leptina/metabolismo , Leptina/farmacología , Obesidad/sangre , Animales , Evolución Biológica , Humanos , Leptina/sangre , Leptina/genética , Ratones , Obesidad/metabolismo , Obesidad/terapiaRESUMEN
Obesity-associated type 2 diabetes mellitus (T2DM) entails insulin resistance and loss of ß-cell mass. Adipose tissue mitochondrial dysfunction is emerging as a key component in the etiology of T2DM. Identifying approaches to preserve mitochondrial function, adipose tissue integrity, and ß-cell mass during obesity is a major challenge. Mitochondrial ferritin (FtMT) is a mitochondrial matrix protein that chelates iron. We sought to determine whether perturbation of adipocyte mitochondria influences energy metabolism during obesity. We used an adipocyte-specific doxycycline-inducible mouse model of FtMT overexpression (FtMT-Adip mice). During a dietary challenge, FtMT-Adip mice are leaner but exhibit glucose intolerance, low adiponectin levels, increased reactive oxygen species damage, and elevated GDF15 and FGF21 levels, indicating metabolically dysfunctional fat. Paradoxically, despite harboring highly dysfunctional fat, transgenic mice display massive ß-cell hyperplasia, reflecting a beneficial mitochondria-induced fat-to-pancreas interorgan signaling axis. This identifies the unique and critical impact that adipocyte mitochondrial dysfunction has on increasing ß-cell mass during obesity-related insulin resistance.