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The product of Aoc3 gene is known as vascular adhesion protein-1 (VAP-1), a glycoprotein contributing to leukocyte extravasation and exhibiting semicarbazide-sensitive amine oxidase activity (SSAO). Regarding the immune functions of VAP-1/SSAO, it is known that mice bearing Aoc3 gene knock-out (AOC3KO) exhibit defects in leukocyte migration similar to those of mice expressing a mutated VAP-1 lacking functional SSAO activity (knock-in, AOC3KI). However, it has not been reported whether these models differ regarding other disturbances. Thus, we further compared endocrine-metabolic phenotypes of AOC3KO and AOC3KI mice to their respective control. Special attention was paid on adiposity, glucose and lipid handling, since VAP-1/SSAO is highly expressed in adipose tissue (AT). In both mouse lines, no tissue SSAO activity was found, while Aoc3 mRNA was absent in AOC3KO only. Although food consumption was unchanged, both AOC3KO and AOC3KI mice were heavier and fatter than their respective controls. Other alterations commonly found in adipocytes from both lines were loss of benzylamine insulin-like action with unchanged insulin lipogenic responsiveness and adiponectin expression. A similar downregulation of inflammatory markers (CD45, IL6) was found in AT. Glucose handling and liver mass remained unchanged, while circulating lipid profile was distinctly altered, with increased cholesterol in AOC3KO only. These results suggest that the lack of oxidase activity found in AOC3KI is sufficient to reproduce the metabolic disturbances observed in AOC3KO mice, save those related with cholesterol transport. Modulation of SSAO activity therefore constitutes a potential target for the treatment of cardiometabolic diseases, especially obesity when complicated by low-grade inflammation.

Various amino acid (AA) metabolites are used as supplements to facilitate metabolic control and enhance responsiveness of insulin-sensitive tissues. β-hydroxy-β-methylbutyrate (HMB) is a leucine metabolite proposed to prevent muscle wasting and to mitigate insulin resistance. Taurine, commonly added to energizing drinks, is a metabolite of methionine and cysteine present in bile juice, and proposed to be involved in lipid digestion and to be pro-lipolytic in adipocytes. N-methyltyramine (NMT) is a phenylalanine metabolite found in orange juices at 0.1–3 ppm while its effects on lipid mobilization remain controversial. Here, the putative lipolytic effects of these AA metabolites were studied and it was tested whether they could enhance insulin antilipolytic response in adipocytes. Release of glycerol and non-esterified fatty acids (NEFAs) was measured after a 2-h incubation of adipocytes obtained from control and diet-induced obese mice or from obese patients. In mouse, none of the tested AA derivatives was lipolytic from 1 μM to 1 mM. These compounds did not improve insulin antilipolytic effect or isoprenaline lipolytic action, except for 1 mM NMT that impaired triacylglycerol breakdown in obese mice. In human adipocytes, HMB and taurine were not lipolytic, while NMT weakly activated glycerol and NEFA release at 1 mM. However, 100 μM NMT impaired isoprenaline-stimulated lipolysis in a manner that was hardly added to insulin antilipolytic effect. Since none of these AA derivatives acutely helped or replaced insulin antilipolytic effect in adipocytes, the present in vitro observations do not support their proposed insulin-sensitizing properties. Moreover, NMT, HMB, and taurine were not notably lipolytic.

Various amino acid (AA) metabolites are used as supplements to facilitate metabolic control and enhance responsiveness of insulin-sensitive tissues. β-hydroxy-β-methylbutyrate (HMB) is a leucine metabolite proposed to prevent muscle wasting and to mitigate insulin resistance. Taurine, commonly added to energizing drinks, is a metabolite of methionine and cysteine present in bile juice, and proposed to be involved in lipid digestion and to be pro-lipolytic in adipocytes. N-methyltyramine (NMT) is a phenylalanine metabolite found in orange juices at 0.1-3 ppm while its effects on lipid mobilization remain controversial. Here, the putative lipolytic effects of these AA metabolites were studied and it was tested whether they could enhance insulin antilipolytic response in adipocytes. Release of glycerol and non-esterified fatty acids (NEFAs) was measured after a 2-h incubation of adipocytes obtained from control and diet-induced obese mice or from obese patients. In mouse, none of the tested AA derivatives was lipolytic from 1 μM to 1 mM. These compounds did not improve insulin antilipolytic effect or isoprenaline lipolytic action, except for 1 mM NMT that impaired triacylglycerol breakdown in obese mice. In human adipocytes, HMB and taurine were not lipolytic, while NMT weakly activated glycerol and NEFA release at 1 mM. However, 100 μM NMT impaired isoprenaline-stimulated lipolysis in a manner that was hardly added to insulin antilipolytic effect. Since none of these AA derivatives acutely helped or replaced insulin antilipolytic effect in adipocytes, the present in vitro observations do not support their proposed insulin-sensitizing properties. Moreover, NMT, HMB, and taurine were not notably lipolytic.

The mechanisms underlying the relationships between nutritional status and immunity remain to be fully characterized. The present study was undertaken to analyze by flow cytometry, in the context of diet-induced obesity, the status of immune cells in subcutaneous, and epididymal fat depots in wild-type and immunodeficient Rag2-/- mice submitted to nutritional challenge, i.e., 48-h fasting and 1-week refeeding. In parallel, the responsiveness of mature adipocytes and immune cells in bone marrow, lymph node, and liver were also analyzed. The results show that fasting in obese wild-type mice induces a prominent lipolysis in epididymal AT and immunosuppression restricted to both subcutaneous and epididymal AT, characterized by reduced number of CD4+ T and B lymphocytes and M1/M2 macrophages associated with reduced leptin and increased FGF21 expression in mature adipocytes. One-week refeeding was sufficient to reverse the fasting-induced effects. Obese immunodeficient mice under nutritional challenge exhibited no changes in adipocyte leptin expression and no marked trafficking of AT macrophages or NK cells, while the fasted-induced upregulation of FGF21 expression was maintained as well as the lipolytic responses. The present results demonstrate that, in a context of diet-induced obesity, fasting-induced immunosuppression is restricted to fat depots in immunocompetent mice. Lack of adipocyte leptin regulation and fasting-induced immunosuppression in obese immunodeficient mice strongly suggests that lymphocytes are involved in the modulation of adipocyte leptin expression on one hand and on the other that leptin is involved in the immune changes in AT according to nutritional status.

Human abdominal adipose tissue (AAT) can be divided into two compartments according to anatomical location to dermis layer, i.e. superficial and deep compartments (sAAT and dAAT). In morbidly obese patients, dAAT mass has been linked to obesity-associated pathologies. In the present study, we characterized in overweight healthy individuals human sAAT and dAAT cellular composition and adipogenic potential. Twelve paired sAAT and dAAT samples were collected. sAAT compared to dAAT adipocytes are larger. In agreement with increased size, real-time PCR analyses performed on isolated adipocytes showed that sAAT adipocytes exhibited higher leptin transcript levels but also higher expression of genes involved in metabolism including hormone-sensitive lipase compared to dAAT adipocytes. Flow cytometry analyses performed on stroma-vascular fraction (SVF) showed no difference in the numbers of progenitor cells, endothelial cells and macrophages between sAAT and dAAT. Macrophage phenotypes were not distinct between both AAT compartments. However, CD3+ T lymphocyte number was higher in dAAT than in sAAT. Adipogenic potential of dAAT SVF was lower than sAAT SVF whereas the one of isolated progenitor cells was not distinct whatever the AAT compartments. Therefore, in overweight patients, both sAAT and dAAT compartments exhibit differences in terms of adipocytes and T lymphocyte accumulation. dAAT is characterized by higher T lymphocyte accumulation together with smaller less metabolically active adipocytes. The lower adipogenic potential of dAAT SVF is not due to intrinsic progenitor cell properties but more likely to the increased T lymphocyte accumulation.