RESUMO
Obesity is a chronic disease caused by excessive fat accumulation that impacts the body and brain health. Insufficient leptin or leptin receptor (LepR) is involved in the disease pathogenesis. Leptin is involved with several neurological processes, and it has crucial developmental roles. We have previously demonstrated that leptin deficiency in early life leads to permanent developmental problems in young adult mice, including an imbalance in energy homeostasis, alterations in melanocortin and the reproductive system and a reduction in brain mass. Given that in humans, obesity has been associated with brain atrophy and cognitive impairment, it is important to determine the long-term consequences of early-life leptin deficiency on brain structure and memory function. Here, we demonstrate that leptin-deficient (LepOb) mice exhibit altered brain volume, decreased neurogenesis and memory impairment. Similar effects were observed in animals that do not express the LepR (LepRNull). Interestingly, restoring the expression of LepR in 10-week-old mice reverses brain atrophy, in addition to neurogenesis and memory impairments in older animals. Our findings indicate that leptin deficiency impairs brain development and memory, which are reversible by restoring leptin signalling in adulthood.
Assuntos
Encéfalo , Leptina , Neurogênese , Receptores para Leptina , Animais , Receptores para Leptina/deficiência , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Camundongos , Encéfalo/metabolismo , Leptina/deficiência , Leptina/metabolismo , Neurogênese/fisiologia , Camundongos Knockout , Camundongos Endogâmicos C57BL , Masculino , Transtornos da Memória/metabolismo , Transtornos da Memória/genética , Atrofia/patologiaRESUMO
Obesity is a pandemic condition of complex etiology, resulting from the increasing exposition to obesogenic environmental factors combined with genetic susceptibility. In the past two decades, advances in genetic research identified variants of the leptin-melanocortin pathway coding for genes, which are related to the potentiation of satiety and hunger, immune system, and fertility. Here, we review cases of congenital leptin deficiency and the possible beneficial effects of leptin replacement therapy. In summary, the cases presented here show clinical phenotypes of disrupted bodily energy homeostasis, biochemical and hormonal disorders, and abnormal immune response. Some phenotypes can be partially reversed by exogenous administration of leptin. With this review, we aim to contribute to the understanding of leptin gene mutations as targets for obesity diagnostics and treatment strategies.
Assuntos
Leptina/uso terapêutico , Obesidade/tratamento farmacológico , Obesidade/genética , Metabolismo Energético/genética , Terapia de Reposição Hormonal , Humanos , Leptina/deficiência , Leptina/genética , Mutação , Obesidade/congênito , FenótipoRESUMO
SUMMARY: Nonalcoholic fatty liver disease (NAFLD) might progress the steatosis to nonalcoholic steatohepatitis (NASH), reaching a cirrhosis state and possibly hepatocellular carcinoma. The liver of three-month-old C57BL/6J mice (wild-type, WT group, n=10) and leptin- deficient obese mice (ob/ob group, n=10) were studied, focusing on the mechanisms associated with the activation of the hepatic stellate cells (HSCs) and pro-fibrogenesis. The obese ob/ob animals' liver showed steatosis, increased lipogenesis gene expressions, inflammation, increased pro-inflammatory gene expressions, inflammatory infiltrate, and potential apoptosis linked to a high Caspase 3 expression. In ob/ob mice, liver sections were labeled in the fibrotic zones by anti-alpha-smooth muscle actin (alpha-SMA) and anti-Reelin, but not in the WT mice. Moreover, the alpha-SMA gene expression was higher in the ob/ob group's liver than the WT group. The pro-fibrogenic gene expressions were parallel to anti- alpha-SMA and anti-Reelin immunofluorescence, suggesting HSCs activation. In the ob/ob animals, there were increased gene expressions involved with lipogenesis (Peroxisome proliferator-activated receptor-gamma, Cell death-inducing DFFA-like effector-c, Sterol regulatory element-binding protein-1c, and Fatty acid synthase), pro-fibrogenesis (Transforming growth factor beta1, Smad proteins- 3, Yes-associated protein-1, Protein platelet-derived growth factor receptor beta), pro-inflammation (Tumor necrosis factor-alpha, and Interleukin-6), and apoptosis (Caspase 3). In conclusion, the results in obese ob/ob animals provide a clue to the events in humans. In a translational view, controlling these targets can help mitigate the hepatic effects of human obesity and NAFLD progression to NASH.
RESUMEN: La enfermedad del hígado graso no alcohólico (HGNA) puede progresar de la esteatosis a esteatohepatitis no alcohólica (ENA), alcanzando un estado de cirrosis y posiblemente carcinoma hepatocelular. Se estudió el hígado de ratones C57BL / 6J de tres meses de edad (tipo salvaje, grupo WT, n = 10) y ratones obesos con deficiencia de leptina (grupo ob/ob, n = 10), centrándose en los mecanismos asociados con la activación de las células estrelladas hepáticas (HSC) y profibrogénesis. El hígado de los animales obesos ob/ob mostró esteatosis, aumento de la expresión génica de la lipogénesis, inflamación, aumento de la expresión génica proinflamatoria, infiltrado inflamatorio y posible apoptosis ligada a una alta expresión de Caspasa 3. En ratones ob/ob, las sec- ciones de hígado se marcaron en las zonas fibróticas con anti-alfa- actina de músculo liso (alfa-SMA) y anti-Reelin, pero no en los ratones WT. Además, la expresión del gen alfa-SMA fue mayor en el hígado del grupo ob/ob que en el grupo WT. Las expresiones génicas profibrogénicas fueron paralelas a la inmunofluorescencia anti-alfa-SMA y anti-Reelin, lo que sugiere la activación de las HSC. En los animales ob/ob, hubo un aumento de las expresiones génicas involucradas con la lipogénesis (receptor activado por proliferador de peroxisoma gamma, efector c similar a DFFA inductor de muerte celular, proteína de unión al elemento regulador de esterol-1c y sintasa de ácidos grasos), pro-fibrogénesis (factor de crecimiento transformante beta 1, proteínas Smad-3, proteína-1 asociada a Yes, receptor beta del factor de crecimiento derivado de plaquetas de proteínas), proinflamación (factor de necrosis tumoral alfa e interleucina-6) y apoptosis (caspasa 3). ). En conclusión, los resultados en animales obesos ob/ob proporcionan una pista de los eventos en humanos. Desde un punto de vista traslacional, el control de estos objetivos puede ayudar a mitigar los efectos hepáticos de la obesidad humana y la progresión de HGNA a ENA.
Assuntos
Animais , Camundongos , Leptina/deficiência , Fígado Gorduroso/patologia , Fotomicrografia , Apoptose , Microscopia Confocal , Lipogênese/genética , Caspase 3/metabolismo , Células Estreladas do Fígado/ultraestrutura , Fígado Gorduroso/genética , Reação em Cadeia da Polimerase em Tempo Real , Hepatopatia Gordurosa não Alcoólica/patologia , Inflamação/genética , Fígado/ultraestrutura , Cirrose Hepática/genética , Cirrose Hepática/patologia , Camundongos Endogâmicos C57BL , ObesidadeRESUMO
Obesity and aging lead to abnormal transforming growth factor-ß1 (TGF-ß1) signaling in the hypothalamus, triggering the imbalance on glucose metabolism and energy homeostasis. Here, we determine the effect of acute exercise on TGF-ß1 expression in the hypothalamus of two models of obesity in mice. The bioinformatics analysis was performed to evaluate the correlation between hypothalamic Tgf-ß1 messenger RNA (mRNA) and genes related to thermogenesis in the brown adipose tissue (BAT) by using a large panel of isogenic BXD mice. Thereafter, leptin-deficient (ob/ob) mice and obese C57BL/6 mice fed on a high-fat diet (HFD) were submitted to the acute exercise protocol. Transcriptomic analysis by using BXD mouse reference population database revealed that hypothalamic Tgf-ß1 mRNA is negatively correlated with genes related to thermogenesis in brown adipose tissue of BXD mice, such as peroxisome proliferator-activated receptor gamma coactivator and is positively correlated with respiratory exchange ratio. In agreement with these results, leptin-deficient (ob/ob) and HFD-fed mice displayed high levels of Tgf-ß1 mRNA in the hypothalamus and reduction of Pgc1α mRNA in BAT. Interestingly, an acute exercise session reduced TGF-ß1 expression in the hypothalamus, increased Pgc1α mRNA in the BAT and reduced food consumption in obese mice. Our results demonstrated that acute physical exercise suppressed hypothalamic TGF-ß1 expression, increasing Pgc1α mRNA in BAT in obese mice.
Assuntos
Regulação para Baixo , Hipotálamo/metabolismo , Obesidade/genética , Condicionamento Físico Animal/fisiologia , Fator de Crescimento Transformador beta1/genética , Tecido Adiposo Marrom/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/genética , Perfilação da Expressão Gênica/métodos , Leptina/deficiência , Leptina/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/etiologia , Obesidade/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Termogênese/genética , Fator de Crescimento Transformador beta1/metabolismoRESUMO
BACKGROUND: Congenital leptin deficiency is a recessive genetic disorder associated with severe early-onset obesity. It is caused by mutations in the leptin (LEP) gene, which encodes the protein product leptin. These mutations may cause nonsense-mediated mRNA decay, defective secretion or the phenomenon of biologically inactive leptin, but typically lead to an absence of circulating leptin, resulting in a rare type of monogenic extreme obesity with intense hyperphagia, and serious metabolic abnormalities. METHODS: We present two severely obese sisters from Colombia, members of the same lineal consanguinity. Their serum leptin was measured by MicroELISA. DNA sequencing was performed on MiSeq equipment (Illumina) of a next-generation sequencing (NGS) panel involving genes related to severe obesity, including LEP. RESULTS: Direct sequencing of the coding region of LEP gene in the sisters revealed a novel homozygous missense mutation in exon 3 [NM_002303.3], C350G>T [p.C117F]. Detailed information and clinical measurements of these sisters were also collected. Their serum leptin levels were undetectable despite their markedly elevated fat mass. CONCLUSIONS: The mutation of LEP, absence of detectable leptin, and the severe obesity found in these sisters provide the first evidence of monogenic leptin deficiency reported in the continents of North and South America.
Assuntos
Leptina/genética , Mutação de Sentido Incorreto/genética , Obesidade Mórbida/genética , Adulto , Colômbia , Consanguinidade , Éxons/genética , Feminino , Humanos , Leptina/deficiência , Obesidade Mórbida/fisiopatologia , Linhagem , IrmãosRESUMO
O treinamento físico aeróbio (TFA) tem sido cada vez mais recomendado para a prevenção e tratamento de comorbidades, que podem ter em comum a resistência periférica à insulina (RI), como o diabetes tipo 2 (DM2) ea obesidade. Caracterizada pelo acúmulo excessivo de tecido adiposo, a obesidade também implica a disfunção endócrina desse tecido. Leptina e adiponectina são hormônios secretados pelos adipócitos que desempenham importante função no metabolismo energético, cujo desequilíbrio está fortemente relacionado à obesidade e à RI. Fisiologicamente, mulheres apresentam maiores níveis de leptina e adiponectina comparados aos de homens. Contudo, em condições como a obesidade e/ou DM2 esses níveis diminuem, deixando o organismo de fêmeas sem os efeitos protetores dessas adipocinas. Assim, o presente estudo teve como objetivo investigar os efeitos do TFA sobre as características morfofuncionais de TAB e pâncreas de camundongos fêmeas com deficiência de leptina. Para isso, camundongos fêmeas com oitosemanas de idade C57BL/J6 selvagem (C57) ou com deficiência de leptina ob/ob (Lepob) foram separadas nos grupos sedentárias (S) e treinadas (T): C57S (n=6), C57T (n=6), LepobS (n=5) e LepobT (n=8). O TFA foi realizadodurante oito semanas, com corrida a 60% da capacidade máxima, 1h/dia, 5x/semana. Água e ração foram administradas ad libitum. Os procedimentos foram aprovados pelo CEUA da EACH-USP (#001/2017). O acompanhamento do peso corporal e consumo de ração foi realizado semanalmente. Na 7ª semana de protocolo foram realizados os testesde tolerância àglicose (TTG) e à insulina (TTI). Ao final do protocolode treinamento foram avaliados parâmetros metabólicos de repouso e de esforço através da calorimetria indireta. A eutanásia dos animais foi realizada cominjeção intraperitoneal de anestésico e, em seguida, foram coletados os tecidos adiposos branco (TAB) subcutâneo e retroperitoneal e a porção esplênica do pâncreas, utilizados, posteriormente, para análises morfológicas. A determinação de adiponectinasérica foi realizada através de kit ELISA. Os resultados foram analisados por ANOVA de duas vias mais o teste post-hoc de Bonferroni. O protocolo de TFA não foi eficaz em reduzir a adiposidade e hiperfagia dos animais LepobS e LepobT, contudo o grupo LepobT apresentou tamanho reduzido de adipócitos doTAB-SC comparado ao grupo LepobS.O TFA não afetouo metabolismo glicêmico dos animais. Os parâmetros metabólicos derepouso não apresentaram alteração, contudo, noteste de esforço físico máximo, o grupo LepobT apresentou maiores tempo em teste até a exaustão e iVO2 comparado ao grupo LepobS. Por fim, embora o TFA não tenha aumentadoa secreção de adiponectina, o que poderia regular positivamente o metabolismo glicêmico de camundongos deficientes em leptina, melhorou a condição metabólica desses animais e reduziu a hipertrofia dos adipócitos do TAB-SC
Aerobic physical training (APT) has become an important strategy for the prevention and treatment of comorbidities, which may have in common the peripheral resistance to insulin(RI), such as type 2 diabetes and obesity. Characterized by the excessive accumulation of adipose tissue, obesity also implies endocrine dysfunction of this tissue.Leptin and adiponectin are hormones secreted by adipocytes that play an important role in energy metabolism, whose imbalance is strongly related to obesity and RI. Physiologically, women have higher levels of leptin and adiponectin compared to men.However,in conditions such as obesity and/or type 2 diabetes these levels decrease, leaving the body of females without the protective effects of these adipokines.Thus, the present study aimed to investigate the effects of APTon the morphofunctional characteristics of white adipose tissue (WAT)and pancreas in leptin-deficientfemale mice. For this, 8-week-old wild C57BL/J6 (C57) or leptin-deficient ob/ob (Lepob) female mice were separated into the groups sedentary (S) and trained (T): C57S (n = 6), C57T (n = 6), LepobS (n = 5) and LepobT (n = 8). Mice were housed in a temperature-controlled (22 ± 2°C) and 12-h light/12-h dark cycle, with free access to tap water and food ad libitum. The APT was performed for 1 h/day at 60% of maximal velocity achieved in the running capacity test, five times per week for eight weeks. The procedures were performed in accordance with the guidelines of the Brazilian College for Animal Experimentation and were approved by the Ethics Committee of the School of Arts, Sciences and Humanities of University of Sao Paulo (Process number001/2017). Body weight and feed intake were evaluated weekly. In the 7th week of protocol, the glucose and insulin tolerance tests (GTT and ITT) were performed. At the end of the training protocol, metabolic parameters of resting and maximal exertion were evaluated through indirect calorimetry. The euthanasia of the animals was performed by intraperitoneal injection of anaesthetic and thenthe subcutaneous and retroperitoneal WAT and the splenic portion of the pancreas were collected, and subsequentlyused for morphological analysis. Serum adiponectin quantification was performed by ELISA kit. The results were analyzed by two-way ANOVA plus the Bonferroni post-hoc test. The APT protocol was not effective in reducing the adiposity and hyperphagia of the animals LepobS and LepobT, however the LepobT group presented a reduced size of WAT-SC adipocytes compared to the LepobS group. Also, APT did not affectthe glycemic metabolism of theseanimals. Although the resting metabolic parameters were not different, in the maximal physical exercise test, the LepobT group had longer time to exhaustion test and iVO2 compared to the LepobS group.Finally, although APTdid not increase adiponectin plasma concentration, which could positively regulate the glycemic metabolism of leptin-deficient mice, it improved the metabolic condition of these animals and reduced the adipocyte hypertrophy of WAT-SC
Assuntos
Animais , Feminino , Camundongos , Exercício Físico/fisiologia , Leptina/deficiência , Resistência à Insulina , Diabetes Mellitus Tipo 2/prevenção & controle , Obesidade/prevenção & controleRESUMO
Leptin is an adipose-derived hormone that controls appetite and energy expenditure. Leptin receptors are expressed on extra-hypothalamic ventrobasal (VB) and reticular thalamic (RTN) nuclei from embryonic stages. Here, we studied the effects of pressure-puff, local application of leptin on both synaptic transmission and action potential properties of thalamic neurons in thalamocortical slices. We used whole-cell patch-clamp recordings of thalamocortical VB neurons from wild-type (WT) and leptin-deficient obese (ob/ob) mice. We observed differences in VB neurons action potentials and synaptic currents kinetics when comparing WT vs. ob/ob. Leptin reduced GABA release onto VB neurons throughout the activation of a JAK2-dependent pathway, without affecting excitatory glutamate transmission. We observed a rapid and reversible reduction by leptin of the number of action potentials of VB neurons via the activation of large conductance Ca2+-dependent potassium channels. These leptin effects were observed in thalamocortical slices from up to 5-week-old WT but not in leptin-deficient obese mice. Results described here suggest the existence of a leptin-mediated trophic modulation of thalamocortical excitability during postnatal development. These findings could contribute to a better understanding of leptin within the thalamocortical system and sleep deficits in obesity.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Leptina/farmacologia , Neurônios/efeitos dos fármacos , Núcleos Talâmicos/citologia , Núcleos Talâmicos/metabolismo , Ácido gama-Aminobutírico/metabolismo , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Animais , Temperatura Corporal/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Janus Quinase 2/metabolismo , Leptina/deficiência , Leptina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/fisiologia , Transdução de Sinais/efeitos dos fármacos , Bloqueadores dos Canais de Sódio/farmacologia , Potenciais Sinápticos/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Tetrodotoxina/farmacologia , Tirfostinas/farmacologiaRESUMO
The clinical manifestations of lipodystrophy syndromes (LS) are hypoleptinemia, hyperglycemia, insulin resistance, dyslipidemia and hepatic steatosis. Leptin replacement therapy (LRT) is effective at improving these pathologies. Currently, there are no data compiling the evidence from the literature, and demonstrating the effect of LRT in LS patients. A systematic review of the MEDLINE and Cochrane Library databases was conducted to identify studies assessing the effect of LRT on metabolic and hepatic endpoints in patients with LS not associated with highly active antiretroviral therapy (HAART) use. Standardized mean differences (SMD) and 95% confidence intervals of pooled results were calculated for overall changes in glucose homeostasis, lipid profile, and hepatic physiology, using an inverse-variance random-effects model. After screening, 12 studies were included for review. Meta-analysis of results from 226 patients showed that LRT decreased fasting glucose [0.75 SMD units (range 0.36-1.13), p=0.0001], HbA1c [0.49 (0.17-0.81), p=0.003], triglycerides [1.00 (0.69-1.31), p<0.00001], total cholesterol [0.62 (0.21-1.02), p=0.003], liver volume [1.06 (0.51-1.61), p=0.0002] and AST [0.41 (0.10-0.73) p=0.01]. In patients with non-HAART LS, LRT improves the outcome of several metabolic and hepatic parameters. Studies were limited by small populations and therefore large prospective trials are needed to validate these findings.
Assuntos
Terapia de Reposição Hormonal , Leptina/uso terapêutico , Lipodistrofia/tratamento farmacológico , Terapia Antirretroviral de Alta Atividade , Glicemia/metabolismo , Colesterol/metabolismo , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Hemoglobinas Glicadas/metabolismo , Humanos , Insulina/metabolismo , Leptina/deficiência , Leptina/metabolismo , Lipodistrofia/metabolismo , Fígado/metabolismo , Albumina Sérica/metabolismo , Síndrome , Transaminases/metabolismo , Triglicerídeos/metabolismoRESUMO
The clinical manifestations of lipodystrophy syndromes (LS) are hypoleptinemia, hyperglycemia, insulin resistance, dyslipidemia and hepatic steatosis. Leptin replacement therapy (LRT) is effective at improving these pathologies. Currently, there are no data compiling the evidence from the literature, and demonstrating the effect of LRT in LS patients. A systematic review of the MEDLINE and Cochrane Library databases was conducted to identify studies assessing the effect of LRT on metabolic and hepatic endpoints in patients with LS not associated with highly active antiretroviral therapy (HAART) use. Standardized mean differences (SMD) and 95% confidence intervals of pooled results were calculated for overall changes in glucose homeostasis, lipid profile, and hepatic physiology, using an inverse-variance random-effects model. After screening, 12 studies were included for review. Meta-analysis of results from 226 patients showed that LRT decreased fasting glucose [0.75 SMD units (range 0.36‐1.13), p=0.0001], HbA1c [0.49 (0.17‐0.81), p=0.003], triglycerides [1.00 (0.69‐1.31), p<0.00001], total cholesterol [0.62 (0.21‐1.02), p=0.003], liver volume [1.06 (0.51‐1.61), p=0.0002] and AST [0.41 (0.10‐0.73) p=0.01]. In patients with non-HAART LS, LRT improves the outcome of several metabolic and hepatic parameters. Studies were limited by small populations and therefore large prospective trials are needed to validate these findings.
As manifestações clínicas das síndromes lipodistróficas (SL) incluem hipoleptinemia, hiperglicemia, resistência insulínica, dislipidemia e esteatose hepática. A terapia de reposição de leptina (TRL) melhora tais parâmetros, mas atualmente não há dados compilados demonstrando tal efeito. Uma revisão sistemática dos bancos de dados MEDLINE e Cochrane Library identificou estudos avaliando os efeitos da TRL sobre parâmetros metabólicos e hepáticos em pacientes com SL não associadas ao uso de antirretrovirais. Diferenças médias padronizadas (DMP) e intervalos de confiança de 95% foram calculados a partir dos resultados, para os efeitos da TRL sobre a homeostase da glicose, perfil lipídico, e morfologia/função hepática, usando um modelo de variação inversa e efeitos randômicos. Após a triagem, 12 estudos foram incluídos para revisão. A metanálise dos resultados de 226 pacientes mostrou que a TRL reduziu a glicemia de jejum [0,75 DMP (amplitude 0,36‐1,13), p=0,0001], HbA1c [0,49 (0,17‐0,81), p=0,003], triglicerídeos [1,00 (0,69‐1,31), p<0,00001], colesterol total [0,62 (0,21‐1,02), p=0,003], volume hepático [1,06 (0,51‐1,61), p=0,0002] e AST [0,41 (0,10‐0,73), p=0,001]. Em pacientes com SL não associada ao uso de antirretrovirais, a TRL melhora vários parâmetros metabólicos e hepáticos. Os estudos avaliados foram limitados pelo pequeno número de pacientes. Maiores estudos clínicos prospectivos são necessários para validar tais achados.
Assuntos
Humanos , Terapia de Reposição Hormonal , Leptina/uso terapêutico , Lipodistrofia/tratamento farmacológico , Terapia Antirretroviral de Alta Atividade , Glicemia/metabolismo , Colesterol/metabolismo , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Hemoglobinas Glicadas/metabolismo , Insulina/metabolismo , Leptina/deficiência , Leptina/metabolismo , Lipodistrofia/metabolismo , Fígado/metabolismo , Síndrome , Albumina Sérica/metabolismo , Transaminases/metabolismo , Triglicerídeos/metabolismoRESUMO
The 72âkDa inositol polyphosphate 5-phosphatase E (72k-5ptase) controls signal transduction through the catalytic dephosphorylation of the 5-position of membrane-bound phosphoinositides. The reduction of 72k-5ptase expression in the hypothalamus results in improved hypothalamic insulin signal transduction and reduction of food intake and body mass. Here, we evaluated the tissue distribution and the impact of obesity on the expression of 72k-5ptase in peripheral tissues of experimental animals. In addition, insulin signal transduction and action were determined in an animal model of obesity and insulin resistance treated with an antisense (AS) oligonucleotide that reduces 72k-5ptase expression. In lean Wistar rats, 72k-5ptase mRNA and protein are found in highest levels in heart, skeletal muscle, and white adipose tissue. In three distinct models of obesity, Wistar rats, Swiss mice fed on high-fat diet, and leptin-deficient ob/ob mice, the expression of 72k-5ptase is increased in skeletal muscle and adipose tissue. The treatment of obese Wistar rats with an anti-72k-5ptase AS oligonucleotide results in significant reduction of 72k-5ptase catalytic activity, which is accompanied by reduced food intake and body mass and improved insulin signal transduction and action as determined by immunoblotting and clamp studies respectively. 72k-5ptase expression is increased in obesity and its AS inhibition resulted in a significant improvement in insulin signal transduction and restoration of glucose homeostasis.