Adipose tissue lymphocytes: types and roles

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Besides adipocytes, specialized in lipid handling and involved in energy balance regulation, white adipose tissue (WAT) is mainly composed of other cell types among which lymphocytes represent a non-negligible proportion. Different types of lymphocytes (B, alphabetaT, ãäT, NK and NKT) have been detected in WAT of rodents or humans, and vary in their relative proportion according to the fat pad anatomical location. The lymphocytes found in intra-abdominal, visceral fat pads seem representative of innate immunity, while those present in subcutaneous fat depots are part of adaptive immunity, at least in mice. Both the number and the activity of the different lymphocyte classes, except B lymphocytes, are modified in obesity. Several of these modifications in the relative proportions of the lymphocyte classes depend on the degree of obesity, or on leptin concentration, or even fat depot anatomical location. Recent studies suggest that alterations of lymphocyte number and composition precede the macrophage increase and the enhanced inflammatory state of WAT found in obesity. Lymphocytes express receptors to adipokines while several proinflammatory chemokines are produced in WAT, rendering intricate crosstalk between fat and immune cells. However, the evidences and controversies available so far are in favour of an involvement of lymphocytes in the control of the number of other cells in WAT, either adipocytes or immune cells and of their secretory and metabolic activities. Therefore, immunotherapy deserves to be considered as a promising approach to treat the endocrino-metabolic disorders associated to excessive fat mass development (AU)

Adipose tissue lymphocytes: types and roles.

Besides adipocytes, specialized in lipid handling and involved in energy balance regulation, white adipose tissue (WAT) is mainly composed of other cell types among which lymphocytes represent a non-negligible proportion. Different types of lymphocytes (B, alphabetaT, gammadeltaT, NK and NKT) have been detected in WAT of rodents or humans, and vary in their relative proportion according to the fat pad anatomical location. The lymphocytes found in intra-abdominal, visceral fat pads seem representative of innate immunity, while those present in subcutaneous fat depots are part of adaptive immunity, at least in mice. Both the number and the activity of the different lymphocyte classes, except B lymphocytes, are modified in obesity. Several of these modifications in the relative proportions of the lymphocyte classes depend on the degree of obesity, or on leptin concentration, or even fat depot anatomical location. Recent studies suggest that alterations of lymphocyte number and composition precede the macrophage increase and the enhanced inflammatory state of WAT found in obesity. Lymphocytes express receptors to adipokines while several proinflammatory chemokines are produced in WAT, rendering intricate crosstalk between fat and immune cells. However, the evidences and controversies available so far are in favour of an involvement of lymphocytes in the control of the number of other cells in WAT, either adipocytes or immune cells and of their secretory and metabolic activities. Therefore, immunotherapy deserves to be considered as a promising approach to treat the endocrino-metabolic disorders associated to excessive fat mass development.

Influence of acute and chronic administration of benzylamine on glucose tolerance in diabetic and obese mice fed on very high-fat diet

The combination of vanadate plus benzylamine has been reported to stimulateglucose transport in rodent adipocytes and to mimic other insulin actions in diversestudies. However, benzylamine alone activates glucose uptake in human fat cells andincreases glucose tolerance in rabbits. The aim of this work was to unravel the benzylamineantihyperglycemic action and to test whether its chronic oral administrationcould restore the defective glucose handling of mice rendered slightly obese anddiabetic by very high-fat diet (VHFD). When VHFD mice were i.p. injected withbenzylamine at 0.7 to 700 ìmol/kg before glucose tolerance test, they exhibitedreduced hyperglycemic response without alteration of insulin secretion. Whole bodyglucose turnover, as assessed by the glucose isotopic dilution technique, wasunchanged in mice perfused with benzylamine (total dose of 75 ìmol/kg). However,their in vivo glycogen synthesis rate was increased. Benzylamine appeared thereforeto directly facilitate glucose utilisation in peripheral tissues. When given chronicallyat 2000 or 4000 ìmol/kg/d in drinking water, benzylamine elicited a slightreduction of water consumption but did not change body weight or adiposity anddid not modify oxidative stress markers. Benzylamine treatment improved glucosa tolerance but failed to normalize the elevated glucose fasting plasma levels of VHFDmice. There was no influence of benzylamine ingestion on lipolytic activity, basal andinsulin-stimulated glucose uptake, and on inflammatory adipokine expression inadipocytes. The improvement of glucose tolerance and the lack of adverse effects onadipocyte metabolism, reported here in VHFD mice allow to consider orally givenbenzylamine as a potential antidiabetic strategy which deserves to be further studied in other diabetic models (AU)

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Influence of acute and chronic administration ofbenzylamine on glucose tolerance in diabetic andobese mice fed on very high-fat diet

The combination of vanadate plus benzylamine has been reported to stimulateglucose transport in rodent adipocytes and to mimic other insulin actions in diversestudies. However, benzylamine alone activates glucose uptake in human fat cells andincreases glucose tolerance in rabbits. The aim of this work was to unravel the benzylamineantihyperglycemic action and to test whether its chronic oral administrationcould restore the defective glucose handling of mice rendered slightly obese anddiabetic by very high-fat diet (VHFD). When VHFD mice were i.p. injected withbenzylamine at 0.7 to 700 ìmol/kg before glucose tolerance test, they exhibitedreduced hyperglycemic response without alteration of insulin secretion. Whole bodyglucose turnover, as assessed by the glucose isotopic dilution technique, wasunchanged in mice perfused with benzylamine (total dose of 75 ìmol/kg). However,their in vivo glycogen synthesis rate was increased. Benzylamine appeared thereforeto directly facilitate glucose utilisation in peripheral tissues. When given chronicallyat 2000 or 4000 ìmol/kg/d in drinking water, benzylamine elicited a slightreduction of water consumption but did not change body weight or adiposity anddid not modify oxidative stress markers. Benzylamine treatment improved glucose tolerance but failed to normalize the elevated glucose fasting plasma levels of VHFDmice. There was no influence of benzylamine ingestion on lipolytic activity, basal andinsulin-stimulated glucose uptake, and on inflammatory adipokine expression inadipocytes. The improvement of glucose tolerance and the lack of adverse effects onadipocyte metabolism, reported here in VHFD mice allow to consider orally givenbenzylamine as a potential antidiabetic strategy which deserves to be further studiedin other diabetic models (AU)

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Reduction of fat deposition by combined inhibition of monoamine oxidases and semicarbazide-sensitive amine oxidases in obese Zucker rats.

Semicarbazide-sensitive amine oxidase (SSAO) and monoamine oxidases (MAO) are highly expressed in adipocytes and generate hydrogen peroxide when activated. Consequently, high concentrations of MAO- or SSAO-substrates acutely stimulate glucose transport and inhibit lipolysis in isolated adipocytes in a hydrogen peroxide-dependent manner. Chronic treatments with MAO and SSAO substrates also increase in vitro adipogenesis and in vivo glucose utilization and fat deposition in diabetic rodents. To further investigate the interplay between amine oxidases, energy balance and fat deposition, prolonged MAO and/or SSAO blockade was performed in obese rats. Pargyline (P, MAO inhibitor), semicarbazide (S, SSAO inhibitor), alone or in combination (P+S), were daily i.p. administered for 3-5 weeks to obese Zucker rats at doses ranging from 20 to 300 micromol/kg. P+S treatments abolished MAO and SSAO activities in any tested tissue. P and S led to a 12-17% reduction of food intake when given in combination but were inactive when given separately. Despite a similar body weight gain reduction in P+S-treated and pair-fed rats, the mitigation of fat deposition was greater in rats receiving both inhibitors. Adipocytes from P+S-treated rats responded as control to insulin but exhibited impaired responses to tyramine, benzylamine or methylamine plus vanadate when considering glucose transport activation or lipolysis inhibition. Although our results did not directly demonstrate that amines are able to spontaneously produce in vivo the insulin-like effects described in vitro, we propose that P+S-induced reduction of fat deposition results from decreased food intake and from impaired MAO- and SSAO-dependent lipogenic and antilipolytic actions of endogenous or alimentary amines.

Semicarbazide-sensitive amine oxidase substrates fail to induce insulin-like effects in fat cells from AOC3 knockout mice.

Substrates of semicarbazide-sensitive amine oxidases (SSAO) stimulate glucose transport in adipocytes. To definitively demonstrate the involvement of SSAO in this insulin-like effect, glucose transport has been studied in fat cells from mice with a targeted deletion of AOC3, a gene encoding a SSAO called vascular adhesion protein-1. SSAO activity was present in white adipose tissues of wild type (WT) but was absent in AOC3KO mice. The SSAO-substrates benzylamine and methylamine were unable to stimulate hexose transport in adipocytes isolated from AOC3KO mice while they were active in WT adipocytes, especially in combination with vanadate. Impairment of amine-dependent glucose uptake was also observed with tyramine while there was no change in insulin responsiveness. These observations prove that the effects of exogenous or biogenic amines on glucose transport are not receptor-mediated but are oxidation-dependent. They also confirm that the major SSAO form expressed in mouse adipocytes is encoded by the AOC3 gene.

Influence of acute and chronic administration of benzylamine on glucose tolerance in diabetic and obese mice fed on very high-fat diet.

The combination of vanadate plus benzylamine has been reported to stimulate glucose transport in rodent adipocytes and to mimic other insulin actions in diverse studies. However, benzylamine alone activates glucose uptake in human fat cells and increases glucose tolerance in rabbits. The aim of this work was to unravel the benzylamine antihyperglycemic action and to test whether its chronic oral administration could restore the defective glucose handling of mice rendered slightly obese and diabetic by very high-fat diet (VHFD). When VHFD mice were i.p. injected with benzylamine at 0.7 to 700 micromol/kg before glucose tolerance test, they exhibited reduced hyperglycemic response without alteration of insulin secretion. Whole body glucose turnover, as assessed by the glucose isotopic dilution technique, was unchanged in mice perfused with benzylamine (total dose of 75 micromol/kg). However, their in vivo glycogen synthesis rate was increased. Benzylamine appeared therefore to directly facilitate glucose utilisation in peripheral tissues. When given chronically at 2000 or 4000 micromol/kg/d in drinking water, benzylamine elicited a slight reduction of water consumption but did not change body weight or adiposity and did not modify oxidative stress markers. Benzylamine treatment improved glucose tolerance but failed to normalize the elevated glucose fasting plasma levels of VHFD mice. There was no influence of benzylamine ingestion on lipolytic activity, basal and insulin-stimulated glucose uptake, and on inflammatory adipokine expression in adipocytes. The improvement of glucose tolerance and the lack of adverse effects on adipocyte metabolism, reported here in VHFD mice allow to consider orally given benzylamine as a potential antidiabetic strategy which deserves to be further studied in other diabetic models.

Increased monoamine oxidase and semicarbazide-sensitive amine oxidase activities in white adipose tissue of obese dogs fed a high-fat diet

Adipocytes express two types of amine oxidases: the cell surface semicarbazidesensitive amine oxidase (SSAO) and the mitochondrial monoamine oxidase (MAO). In human abdominal subcutaneous adipose tissue, it has been reported that SSAO substrates stimulate glucose transport and inhibit lipolysis while MAO activity is decreased in obese patients when compared to age-matched controls. However, no information has been reported on visceral WAT. To further investigate the obesity-induced regulations of MAO and SSAO in white adipose tissue (WAT) from different anatomical locations, enzyme activities and mRNA abundance have been determined on tissue biopsies from control and high-fat fed dogs, an obesity model already described to be associated with arterial hypertension and hyperinsulinemia. MAO activity was increased in the enlarged omental WAT of diet-induced obese dogs, but not in their mesenteric WAT, another intra-abdominal fat depot. Subcutaneous WAT did not exhibit any change in MAO activity, as did the richest MAO-containing tissue: liver. Similarly, SSAO was increased in omental WAT of diet-induced obese dogs, but was not modified in other WAT and in aorta. The increase in SSAO activity observed in omental WAT likely results from an increased expression of the AOC3 gene since mRNA abundance and maximal benzylamine oxidation velocity were increased. Finally, plasma SSAO was decreased in obese dogs. Although the observed regulations differ from those found in subcutaneous WAT of obese patients, this canine model shows a tissue- and site-specific regulation of peripheral MAO and SSAO in obesity (AU)

Los adipocitos expresan dos tipos de amino-oxidasa: la amino oxidasa sensible a semicarbazida de la superficie celular (SSAO) y la monoamino oxidasa mitocondrial (MAO). En el tejido adiposo subcutáneo abdominal de humanos se ha descrito que los sustratos de la SSAO estimulan el transporte de glucosa e inhiben la lipólisis, mientras que la actividad MAO disminuye en pacientes obesos cuando se compara con controles de su propia edad. Sin embargo, no existe información sobre lo que ocurre en el tejido adiposo visceral. Se investiga, por tanto, sobre la influencia de la obesidad en la regulación de la MAO y SSAO en el tejido adiposo blanco (WAT) de diferentes localizaciones anatomicas, su actividad enzimatica y la riqueza de RNAm en biopsias tisulares procedentes de perros control y tratados con dieta rica en grasa. Este modelo de obesidad ya había sido previamente descrito asociado a hipertensión arterial e hiperinsulinemia. La actividad MAO se incrementó en WAT omental hipertrofiado de perros tratados con dieta rica en grasa, pero este efecto no se apreciaba en su correspondiente tejido adiposo mesentérico, otro depósito graso intra-abdominal. En el tejido adiposo subcutáneo no se pusieron de manifiesto cambios en la actividad MAO, ni tampoco en un tejido como el hígado, muy rico en MAO.De forma similar, la actividad SSAO se incrementó en el WAT omental de perros con obesidad inducida por la dieta, pero no se modificaba en otros WAT y en la aorta. El incremento encontrado en la actividad de la SSAO en el WAT (..) (AU)

Prolonged treatment with the beta3-adrenergic agonist CL 316243 induces adipose tissue remodeling in rat but not in guinea pig: 2) modulation of glucose uptake and monoamine oxidase activity.

Beta3-adrenergic agonists are well-recognited to promote lipid mobilisation and adipose tissue remodeling in rodents, leading to multilocular fat cells enriched in mitochondria. However, effects of beta3-adrenergic agonists on glucose transport are still controversial. In this work, we studied in white adipose tissue (WAT) the influence of sustained beta3-adrenergic stimulation on the glucose transport and on the mitochondrial monoamine oxidase (MAO) activity. As one-week administration of CL 316243 (CL, 1 mg/kg/d) induces beta-adrenergic desensitization in rat but not in guinea pig adipocytes, attention was paid to compare these models. When expressing glucose uptake as nmoles of 2-deoxyglucose/100 mg cell lipids, maximally stimulated uptake was increased in adipocytes of WAT from treated rats but not from treated guinea pigs. However, basal hexose uptake was also increased in CL-treated rats and, as a consequence, the dose-dependent curves for insulin stimulation were similar in control and CL-treated rats when expressed as fold increase over basal. Insulin-induced lipogenesis was unchanged in rat or guinea pig adipocytes after CL-treatment. The glucose carriers GLUT4 and corresponding mRNA were increased in subcutaneous WAT or in brown adipose tissue (BAT) but not in visceral WAT or muscles of CL-treated rats. There was an increase of MAO activity in WAT and BAT, but not in liver, of CL-treated rats while no change was detected in guinea pigs. These findings show that only rat adipocytes, which are beta3-adrenergic-responsive, respond to chronic beta3-AR agonist by an increase of GLUT4 content and MAO activity, despite a desensitization of all beta-adrenoceptor subtypes.

Increased monoamine oxidase and semicarbazide-sensitive amine oxidase activities in white adipose tissue of obese dogs fed a high-fat diet.

Adipocytes express two types of amine oxidases: the cell surface semicarbazide-sensitive amine oxidase (SSAO) and the mitochondrial monoamine oxidase (MAO). In human abdominal subcutaneous adipose tissue, it has been reported that SSAO substrates stimulate glucose transport and inhibit lipolysis while MAO activity is decreased in obese patients when compared to age-matched controls. However, no information has been reported on visceral WAT. To further investigate the obesity-induced regulations of MAO and SSAO in white adipose tissue (WAT) from different anatomical locations, enzyme activities and mRNA abundance have been determined on tissue biopsies from control and high-fat fed dogs, an obesity model already described to be associated with arterial hypertension and hyperinsulinemia. MAO activity was increased in the enlarged omental WAT of diet-induced obese dogs, but not in their mesenteric WAT, another intra-abdominal fat depot. Subcutaneous WAT did not exhibit any change in MAO activity, as did the richest MAO-containing tissue: liver. Similarly, SSAO was increased in omental WAT of diet-induced obese dogs, but was not modified in other WAT and in aorta. The increase in SSAO activity observed in omental WAT likely results from an increased expression of the AOC3 gene since mRNA abundance and maximal benzylamine oxidation velocity were increased. Finally, plasma SSAO was decreased in obese dogs. Although the observed regulations differ from those found in subcutaneous WAT of obese patients, this canine model shows a tissue- and site-specific regulation of peripheral MAO and SSAO in obesity.

Influence of high-fat diet on amine oxidase activity in white adipose tissue of mice prone or resistant to diet-induced obesity.

Decreased monoamine oxidase (MAO) activity has been observed in adipose tissue of obese patients. Since substrates of MAO and semicarbazide-sensitive amine oxidase (SSAO) can modify adipocyte metabolism, this work investigates whether changes in amine oxidase activity may occur during white adipose tissue (WAT) development. We evaluated MAO and SSAO activities in WAT of high-fat diet (HFD) and low-fat diet fed mice. To distinguish the effect of HFD on its own from the effect of fat mass enlargement, obesity-prone transgenic line of the FVBn strain lacking beta3-adrenergic receptors (AR) but expressing human beta3-AR and alpha2-AR (mbeta3-/-, hbeta3+/+, halpha2+/-) was compared to its obesity-resistant control (mbeta3-/-, hbeta3+/+). As already reported, the former mice became obese while the latter resisted to HFD. No significant change in SSAO or MAO activity was found in WAT of both strains after HFD when expressing oxidase activity per milligram of protein. However, when considering the overall capacity of the fat depots to oxidize tyramine or benzylamine, there was an increase in MAO and SSAO activity only in the enlarged WAT of HFD-induced obese mice. Therefore, the comparison of these models allowed to demonstrate that the higher amine oxidase capacity hold in enlarged fat stores of obese mice is more likely the consequence of increased fat cell number rather than the result of an increased expression of MAO or SSAO in the adipocyte.

Effects of oral administration of benzylamine on glucose tolerance and lipid metabolism in rats.

Repeated administration of benzylamine plus vanadate have been reported to exhibit anti-hyperglycemic effects in different models of diabetic rats. Likewise oral treatment with Moringa oleifera extracts which contain the alkaloïd moringine, identical to benzylamine, has also been shown to prevent hyperglycemia in alloxan-induced diabetic rats. With these observations we tested whether prolonged oral administration of benzylamine could interact with glucose and/or lipid metabolism. Seven week old male Wistar rats were treated for seven weeks with benzylamine 2.9 g/l in drinking water and were submitted to glucose tolerance tests. A slight decrease in water consumption was observed in benzylamine-treated animals while there was no change in body and adipose tissue weights at the end of treatment. Blood glucose and plasma insulin, triacylglycerol or cholesterol levels were not modified. However, benzylamine treatment resulted in a decrease in plasma free fatty acids in both fed and fasted conditions. Benzylamine treatment improved glucose tolerance as shown by the reduction of hyperglycemic response to intra-peritoneal glucose load. Oral benzylamine treatment did not alter the response of adipocytes to insulin nor to insulin-like actions of benzylamine plus vanadate, via in vitro activation of glucose transport or inhibition of lipolysis. This work demonstrates for the first time that oral administration of benzylamine alone influences glucose and lipid metabolism. However, these results obtained in normoglycemic rats require to be confirmed in diabetic models.

Amine oxidase substrates for impaired glucose tolerance correction.

Amine oxidases are widely distributed from microorganisms to vertebrates and produce hydrogen peroxide plus aldehyde when catabolizing endogenous or xenobiotic amines. Novel roles have been attributed to several members of the amine oxidase families, which cannot be anymore considered as simple amine scavengers. Semicarbazide-sensitive amine oxidase (SSAO) is abundantly expressed in mammalian endothelial, smooth muscle, and fat cells, and plays a role in lymphocyte adhesion to vascular wall, arterial fiber elastic maturation, and glucose transport, respectively. This latter role was studied in detail and the perspectives of insulin-like actions of amine oxidase substrates are discussed in the present review. Independent studies have demonstrated that SSAO substrates and monoamine oxidase substrates mimic diverse insulin effects in adipocytes: glucose transport activation, lipogenesis stimulation and lipolysis inhibition. These substrates also stimulate in vitro adipogenesis. Acute in vivo administration of amine oxidase substrates improves glucose tolerance in rats, mice and rabbits, while chronic treatments with benzylamine plus vanadate exert an antihyperglycaemic effect in diabetic rats. Dietary supplementations with methylamine, benzylamine or tyramine have been proven to influence metabolic control in rodents by increasing glucose tolerance or decreasing lipid mobilisation, without noticeable changes in the plasma markers of lipid peroxidation or protein glycation, despite adverse effects on vasculature. Thus, the ingested amines are not totally metabolized at the intestinal level and can act on adipose and vascular tissues. In regard with this influence on metabolic control, more attention must be paid to the composition or supplementation in amines in foods and nutraceutics.

Influence of high-fat diet on amine oxidase activity in white adipose tissue of mice prone or resistant to diet-induced obesity

Decreased monoamine oxidase (MAO) activity has been observed in adipose tissue of obese patients. Since substrates of MAO and semicarbazide-sensitive amine oxidase (SSAO) can modify adipocyte metabolism, this work investigates whether changes in amine oxidase activity may occur during white adipose tissue (WAT) development. We evaluated MAO and SSAO activities in WAT of high-fat diet (HFD) and low-fat diet fed mice. To distinguish the effect of HFD on its own from the effect of fat mass enlargement, obesity-prone transgenic line of the FVBn strain lacking b3-adrenergic receptors (AR) but expressing human b3-AR and a2-AR (mb3-/-, hb3+/+, ha2+/-) was compared to its obesity-resistant control (mb3-/-, hb3+/+). As already reported, the former mice became obese while the latter resisted to HFD. No significant change in SSAO or MAO activity was found in WAT of both strains after HFD when expressing oxidase activity per milligram of protein. However, when considering the overall capacity of the fat depots to oxidize tyramine or benzylamine, there was an increase in MAO and SSAO activity only in the enlarged WAT of HFD-induced obese mice. Therefore, the comparison of these models allowed to demonstrate that the higher amine oxidase capacity hold in enlarged fat stores of obese mice is more likely the consequence of increased fat cell number rather than the result of an increased expression of MAO or SSAO in the adipocyte

En trabajos previos se describe que la actividad monoamino oxidasa (MAO) en el tejido adiposo disminuye en pacientes obesos. Dado que los sustratos de la MAO y de la amino oxidasa sensible a semicarbazida (SSAO) pueden modificar el metabolismo de los adipocitos, se investiga en este trabajo si se producen cambios en la actividad amino oxidasa durante el desarrollo del tejido adiposo blanco. Para ello, se evalúa el efecto de la dieta rica en grasa (HFD) respecto de la dieta control sobre la actividad MAO y SSAO en tejido adiposo de ratones transgénicos que no expresan sus propios receptores adrenérgicos b3 y que son de dos líneas diferentes: los que expresan los receptores adrenérgicos humanos b3 Y a2 (mb3 -/-, hb3+/+, ha2+/-) y que son no susceptibles a la obesidad y los que sólo expresan los b3 humanos (mb3 -/-, hb3+/+) y que son resistentes a la obesidad. Los resultados no muestran cambios significativos por efecto de la dieta en ninguno de los dos grupos de ratones sobre la actividad MAO y SSAO cuando se expresa referida a mg de proteína. Sin embargo, cuando se considera la capacidad total de los depósitos grasos para oxidar tiramina o benzilamina, so observa un aumento significativo en ambas actividades MAO y SSAO sólo en el incrementado tejido adiposo blanco de los ratones obesos por efecto de la dieta HFD. Por tanto, estos datos indican que la mayor actividad amino oxidasa de los depósitos grasos de los ratones obesos es probablemente debida al aumento del número de células adiposas, mas que a un incremento de la expresión de MAO y SSAO en los adipocitos

Effects of oral administration of benzylamine on glucose tolerance and lipid metabolism in rats

Repeated administration of benzylamine plus vanadate have been reported to exhibit anti-hyperglycemic effects in different models of diabetic rats. Likewise oral treatment with Moringa oleifera extracts which contain the alkaloïd moringine, identical to benzylamine, has also been shown to prevent hyperglycemia in alloxan-induced diabetic rats. With these observations we tested whether prolonged oral administration of benzylamine could interact with glucose and/or lipid metabolism. Seven week old male Wistar rats were treated for seven weeks with benzylamine 2.9 g/l in drinking water and were submitted to glucose tolerance tests. A slight decrease in water consumption was observed in benzylamine-treated animals while there was no change in body and adipose tissue weights at the end of treatment. Blood glucose and plasma insulin, triacylglycerol or cholesterol levels were not modified. However, benzylamine treatment resulted in a decrease in plasma free fatty acids in both fed and fasted conditions. Benzylamine treatment improved glucose tolerance as shown by the reduction of hyperglycemic response to intra-peritoneal glucose load. Oral benzylamine treatment did not alter the response of adipocytes to insulin nor to insulin-like actions of benzylamine plus vanadate, via in vitro activation of glucose transport or inhibition of lipolysis. This work demonstrates for the first time that oral administration of benzylamine alone influences glucose and lipid metabolism. However, these results obtained in normoglycemic rats require to be confirmed in diabetic models

En ratas diabéticas, la administración crónica de la combinación benzilamina más vanadato ejerce un efecto antidiabético. Recientemente se ha descrito en ratas diabéticas inducidas por aloxan una reducción de la glucemia tras el tratamiento oral con extracto de Moringa oleifera, que contiene el alcaloide moringina, idéntico a la benzilamina. Por ello, se investiga en este trabajo el efecto del tratamiento prolongado por via oral con sólo benzilamina sobre el metabolismo de la glucosa y/o los lípidos. Ratas macho Wistar de 7 semanas se trataron durante 7 semanas con benzilamina 2.9 g/l en el agua de la bebida. Al finalizar el tratamiento, las ratas fueron sometidos a un test de tolerancia a la glucosa, inyectada por via intraperitoneal. Se recogió plasma para la determinación bioquímica y se aislaron adipocitos para estudiar la lipólisis y la captación de glucosa. El tratamiento oral con benzilamina no modifica el peso corporal ni el de la grasa, ni los niveles plasmáticos de glucosa, insulina, triacilglicerol y colesterol. Sin embargo, mejora la tolerancia a la glucosa, pues reduce la respuesta hiperglucémica a la inyección intra-peritoneal de glucosa y reduce los niveles de acidos grasos, tanto en situación de ayuno como tras la ingesta. El tratamiento oral con benzilamina no modifica en el adipocito los efectos de insulina o benzilamina más vanadato sobre la activación del transporte de glucosa o la inhibición de la lipolisis. Este trabajo demuestra por vez primera que la administración oral de benzilamina influye sobre el metabolismo de los lípidos y de la glucosa. Sin embargo, estos resultados obtenidos en ratas normoglicémicas deben ser confirmados en modelos diabéticos

Amine oxidase substrates for impaired glucose tolerance correction

Amine oxidases are widely distributed from microorganisms to vertebrates and produce hydrogen peroxide plus aldehyde when catabolizing endogenous or xenobiotic amines. Novel roles have been attributed to several members of the amine oxidase families, which cannot be anymore considered as simple amine scavengers. Semicarbazide-sensitive amine oxidase (SSAO) is abundantly expressed in mammalian endothelial, smooth muscle, and fat cells, and plays a role in lymphocyte adhesion to vascular wall, arterial fiber elastic maturation, and glucose transport, respectively. This latter role was studied in detail and the perspectives of insulin-like actions of amine oxidase substrates discussed in the present review. Independent studies have demonstrated that SSAO substrates and monoamine oxidase substrates mimic diverse insulin effects in adipocytes: glucose transport activation, lipogenesis stimulation and lipolysis inhibition. These substrates also stimulate in vitro adipogenesis. Acute in vivo administration of amine oxidase substrates improves glucose tolerance in rats, mice and rabbits, while chronic treatments with benzylamine plus vanadate exert an antihyperglycaemic effect in diabetic rats. Dietary supplementations with methylamine, benzylamine or tyramine have been proven to influence metabolic control in rodents by increasing glucose tolerance or decreasing lipid mobilisation, without noticeable changes in the plasma markers of lipid peroxidation or protein glycation, despite adverse effects on vasculature. Thus, the ingested amines are not totally metabolized at the intestinal level and can act on adipose and vascular tissues. In regard with this influence on metabolic control, more attention must be paid to the composition or supplementation in amines in foods and nutraceutics

Las amino-oxidasas (AO) están ampliamente distribuidas, desde microorganismos hasta vertebrados, y producen peróxido de hidrógeno y aldehído al catabolizar aminas biógenas o exógenas. Datos recientes ponen de manifiesto que las AO no pueden considerarse exclusivamente como depuradoras de aminas. La amino-oxidasa sensible a semicarbazida (SSAO) es muy abundante en ciertas células de mamíferos como las endoteliales, la célula muscular lisa y los adipocitos, donde desempeña un papel importante en la adhesión de los linfocitos a las paredes vasculares, la maduración de las fibras elásticas arteriales, y el transporte de glucosa, respectivamente. Este último efecto es el que se presenta en esta revisión donde, además, se discuten las perspectivas abiertas como consecuencia de sus acciones insulino-miméticas. Los sustratos de SSAO y de monoamino-oxidasa mimetizan varios efectos de la insulina en los adipocitos: activación del transporte de glucosa y de la lipogénesis e inhibición de la lipólisis. También estimulan in vitro la adipogénesis. La administración aguda in vivo de sustratos de AO mejora la tolerancia a la glucosa en ratas, ratones y conejos, y los tratamientos crónicos con benzilamina y vanadato tienen un efecto antihiperglucemiante en ratas diabéticas. Suplementos en la dieta con metilamina, benzilamina o tiramina han puesto de manifiesto una acción beneficiosa sobre el control metabólico en roedores a través de un aumento en la tolerancia a la glucosa o una disminución de la movilización lipídica, sin cambios notables en los marcadores plasmáticos de peroxidación lipídica o de glicación proteica, a pesar de unos efectos aterogénicos indeseables. Por tanto, las aminas ingeridas no se degradan totalmente a nivel de la barrera intestinal y pueden actuar sobre el tejido adiposo y vascular. En relación con esta influencia sobre el control metabólico, se concluye que es necesario prestar atención a la composición o adición como suplementos de estas aminas a los alimentos y medicamentos

Moderate weight-lowering effect of octopamine treatment in obese Zucker rats.

Octopamine is proposed as a substitution product of synephrine by diverse drug industries that advertise new weight-lowering products or medicinal plants enriched in this biogenic amine. We have already reported that octopamine is able to activate in vitro lipolysis in rat adipocytes via beta3-adrenergic receptor activation, while it activates glucose uptake in human fat cells via its oxidation by amine oxidases. In this work, we tested whether a chronic challenge with octopamine could exert anti-obesity effects. A treatment consisting in daily i.p. administration of octopamine (81 micromol/kg) was compared on a four-week period with calorie restriction in the genetically obese Zucker rat. Octopamine treatment resulted in a 19% decrease in body weight gain, when compared to the 177 g gained by controls during the same period. The decrease in body weight gain was detectable only after three weeks of treatment and was apparently not due to a pronounced and sustainable anorectic effect of octopamine since: 1) cumulated food consumption was only reduced by 10%; 2) the experimental 18% reduction of food intake provoked a rapid decrease in body weight gain, significant in less than two weeks. The lipolytic responses to isoprenaline or octopamine and the stimulation of glucose transport by insulin or by the amine oxidase substrate tyramine were unmodified by the treatments. Noteworthy, the elevated plasma insulin of obese rats was lowered by octopamine. This study shows that octopamine can reduce body weight gain in obese rats, without apparent adverse effects, but with less efficacy than beta3-AR agonists.