RESUMO
The major form of primary amine oxidase expressed in adipose tissue (AT) is encoded by AOC3 gene and is known as semicarbazide-sensitive amine oxidase, identical to vascular adhesion protein-1 (SSAO/VAP-1). Exogenous substrates of SSAO/VAP-1 (e.g. benzylamine) stimulate glucose transport in adipocytes and improve glucose tolerance when injected in diabetic rodents. Numerous reports on the circulating, soluble SSAO/VAP-1 have univocally evidenced an increase in diabetic conditions. However, only scarce studies have investigated whether obesity and/or diabetes is accompanied with variations of AOC3 expression in AT. Therefore, we compared the SSAO/VAP-1 content in different fat depots of db-/- mice (lacking leptin receptor and being hyperphagic, diabetic and obese) and db+/- littermates (normoglycemic and lean). AOC3 expression was increased in perigonadal and subcutaneous AT of db-/- mice, while the maximal velocity of benzylamine oxidation (V (max), expressed as pmoles of hydrogen peroxide produced/min/mg protein) increased only in the latter. Indeed, the relative abundance of primary amine oxidase was increased in subcutaneous AT of db-/- mice at all the levels: mRNA, protein and activity. While considering the overall capacity to oxidise amines contained in each depot, there was an increase in the hypertrophic fat pads of the obese db-/- mice, irrespective of their anatomical location, as a result of their dramatically larger mass than in lean db+/- control. Such higher amount of AT-bound primary amine oxidase warrants further studies to determine whether SSAO/VAP-1 inhibition or activation may be useful in treating metabolic diseases.
Assuntos
Tecido Adiposo Branco/enzimologia , Amina Oxidase (contendo Cobre)/biossíntese , Moléculas de Adesão Celular/biossíntese , Complicações do Diabetes/enzimologia , Obesidade/enzimologia , Amina Oxidase (contendo Cobre)/genética , Animais , Moléculas de Adesão Celular/genética , Complicações do Diabetes/genética , Ativação Enzimática/genética , Feminino , Masculino , Camundongos , Camundongos Knockout , Camundongos Mutantes , Camundongos Obesos , Obesidade/genética , Regulação para Cima/genéticaRESUMO
The aspartic protease cathepsin-D (cath-D) is overexpressed by human epithelial breast cancer cells and is closely correlated with poor prognosis in breast cancer. The adipocyte is one of the most prominent cell types in the tumor-microenvironment of breast cancer, and clinical studies have shown that obesity increases the incidence of breast cancer. Here, we provide the first evidence that cath-D expression is up-regulated in adipose tissue from obese human beings, as well as in adipocytes from the obese C57BI6/J mouse. Cath-D expression is also increased during human and mouse adipocyte differentiation. We show that cath-D silencing in 3T3-F442A murine preadipocytes leads to lipid-depleted cells after adipogenesis induction, and inhibits of the expression of PPARγ, HSL and aP2 adipocyte differentiation markers. Altogether, our findings demonstrate the key role of cath-D in the control of adipogenesis, and suggest that cath-D may be a novel target in obesity.
Assuntos
Adipogenia/genética , Tecido Adiposo/metabolismo , Catepsina D/genética , Obesidade/genética , Células 3T3 , Adipócitos/metabolismo , Adipócitos/patologia , Adipogenia/fisiologia , Tecido Adiposo/patologia , Animais , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Carcinoma/enzimologia , Carcinoma/genética , Catepsina D/metabolismo , Catepsina D/fisiologia , Células Cultivadas , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Regulação Enzimológica da Expressão Gênica/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/enzimologia , Obesidade/patologia , PPAR gama/genética , PPAR gama/metabolismo , Peptídeo Hidrolases/genética , Peptídeo Hidrolases/metabolismo , Peptídeo Hidrolases/fisiologia , Regulação para CimaRESUMO
The cell surface low-density lipoprotein receptor-related protein 1, LRP1, plays a major role in lipid metabolism. The question that remains open concerns the function of LRP1 in adipogenesis. Here, we show that LRP1 is highly expressed in murine preadipocytes as well as in primary culture of human adipocytes. Moreover, LRP1 remains abundantly synthesised during mouse and human adipocyte differentiation. We demonstrate that LRP1 silencing in 3T3F442A murine preadipocytes significantly inhibits the expression of PPARgamma, HSL and aP2 adipocyte differentiation markers after adipogenesis induction, and leads to lipid-depleted cells. We further show that the absence of lipids in LRP1-silenced preadipocytes is not caused by lipolysis induction. In addition, we provide the first evidences that LRP1 is significantly up-regulated in obese C57BI6/J mouse adipocytes and obese human adipose tissues. Interestingly, silencing of LRP1 in fully-differentiated adipocytes also reduces cellular lipid level and is associated with an increase of basal lipolysis. However, the ability of mature adipocytes to induce lipolysis is independent of LRP1 expression. Altogether, our findings highlight the dual role of LRP1 in the control of adipogenesis and lipid homeostasis, and suggest that LRP1 may be an important therapeutic target in obesity.
