The components required for amino acid neurotransmitter signaling are present in adipose tissues

Abstract

The adipocyte does not only serve as fuel storage but produces and secretes compounds with modulating effects on food intake and energy homeostasis. Although there is firm evidence for a centrally mediated regulation of adipocyte function via the autonomous nervous system, little is known about signaling between adipocytes. Amino acid neurotransmitters are candidates for such paracrine signaling. Here, we applied immunohistochemistry to detect components required for amino acid transmitter signaling in rat fat depots. In interscapular brown adipose tissue as well as in interscapular, mesenteric, perirenal, and epididymal white adipose tissues, we demonstrate robust immunosignals for the excitatory neurotransmitter glutamate, the inhibitory neurotransmitter g-aminobutyric acid (GABA), and the GABA-synthesizing enzyme glutamate decarboxylase (GAD) isoforms GAD65 and GAD67. Moreover, all adipose tissues stained for the vesicular glutamate transporter VGLUT1 and the vesicular GABA transporter VGAT in addition to the vesicle marker synaptophysin. Electron microscopic immunocytochemistry showed that VGLUT1 and VGAT, but not VGLUT2 or VGLUT3, are localized in vesicular organelles in adipocytes. The receptors for glutamate (subunits GluR2/3 and NR1 but not mGluR2) and for GABA (GABA A Ra2) were present in the adipocytes. The presence of glutamate, GABA, their vesicular transporters, and their receptors indicates a paracrine signaling role for amino acids in adipose tissues.-Nicolaysen, A., R. Gammelsaeter, J. Storm-Mathisen, V. Gundersen, and P. O. Iversen. The components required for amino acid neurotransmitter signaling are present in adipose tissues. J. Lipid

Oral Treatment with γ-Aminobutyric Acid Improves Glucose Tolerance and Insulin Sensitivity by Inhibiting Inflammation in High Fat Diet-Fed Mice

“…GABA A -R subunits are expressed by immunocompetent cells, including T cells and macrophages and are also expressed by adipose tissues [13], [14], [15], [17]. Our previous studies and those of others have shown that treatment with GABA or a GABA A receptor agonist inhibits inflammation in different mouse models of autoimmune diseases [16], [17], [18], [20], [21].…”

“…Given that GABA A -R subunits are expressed by macrophages and adipose tissues [13], [15], we further tested whether GABA could modulate macrophage-associated inflammation in adipose tissues, or alter adipose tissue mass in the HFD-fed mice. Following HFD feeding for 20 weeks, control and GABA-treated mice were sacrificed and their VAT was dissected out and weighed.…”

“…We found that oral treatment with GABA significantly decreased the frequency of macrophage infiltrates in adipose tissues of the HFD-fed mice. More importantly, GABA A receptor subunits are expressed by adipocytes and macrophages, and GABA A receptor agonists can inhibit macrophage activation [13], [15], [17]. It is possible that GABA, through the GABA A receptors, inhibits macrophage activation and migration, reducing chronic inflammation in adipose tissues.…”

“…Indeed, regulatory T cells (Tregs) have been shown to inhibit the high fat diet (HFD)-induced adipocyte dysfunction, glucose intolerance, and insulin resistance in mice [12]. Notably, GABA A receptors (GABA A -R) are expressed by adipose tissues and immunocompetent cells, such as macrophages and T cells [13], [14], [15]. Our previous studies and those of others have shown that activation of GABA A -R inhibits inflammatory diseases, such as type 1 diabetes (T1D), experimental autoimmune encephalomyelitis (EAE), collagen-induced rheumatoid arthritis (RA) in mice and prolongs the survival of syngenic islet grafts in diabetic NOD mice [16], [17], [18], [19], [20].…”

Recent advances in the understanding of how neuropeptide Y andα-melanocyte stimulating hormone function in adipose physiology

“…97 Other amino acid neurotransmitters are also found in the adipose tissue; with immunohistochemical labeling used to detect gamma amino butyric acid (GABA), glutamate, the GABA producing enzyme glutamate decarboxylase, and transporters and receptors for glutamate and GABA. 98 There is also regulation by POMC peptides in adipose tissue to promote browning of WAT and lipolysis, 99,100 and sympathetic innervation of the adipose tissue. 101 The neurotransmitter NPY has received much attention in recent years, highlighted in our recent review, 18 but is still an active area of research, which is reviewed herein.…”