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

Abstract

Adipocyte and β-cell dysfunction and macrophage-related chronic inflammation are critical for the development of obesity-related insulin resistance and type 2 diabetes mellitus (T2DM), which can be negatively regulated by Tregs. Our previous studies and those of others have shown that activation of γ-aminobutyric acid (GABA) receptors inhibits inflammation in mice. However, whether GABA could modulate high fat diet (HFD)-induced obesity, glucose intolerance and insulin resistance has not been explored. Here, we show that although oral treatment with GABA does not affect water and food consumption it inhibits the HFD-induced gain in body weights in C57BL/6 mice. Furthermore, oral treatment with GABA significantly reduced the concentrations of fasting blood glucose, and improved glucose tolerance and insulin sensitivity in the HFD-fed mice. More importantly, after the onset of obesity and T2DM, oral treatment with GABA inhibited the continual HFD-induced gain in body weights, reduced the concentrations of fasting blood glucose and improved glucose tolerance and insulin sensitivity in mice. In addition, oral treatment with GABA reduced the epididymal fat mass, adipocyte size, and the frequency of macrophage infiltrates in the adipose tissues of HFD-fed mice. Notably, oral treatment with GABA significantly increased the frequency of CD4+Foxp3+ Tregs in mice. Collectively, our data indicated that activation of peripheral GABA receptors inhibited the HFD-induced glucose intolerance, insulin resistance, and obesity by inhibiting obesity-related inflammation and up-regulating Treg responses in vivo. Given that GABA is safe for human consumption, activators of GABA receptors may be valuable for the prevention of obesity and intervention of T2DM in the clinic.

Immunological GABAergic interactions and therapeutic applications in autoimmune diseases

“…Tian, et al [50], examined obesity and hyperglycemia in high fat diet-fed mice. In these mice obesity-related inflammation appears to be a major pathogenic factor.…”

GABA Promotes Human β-Cell Proliferation and Modulates Glucose Homeostasis

“…In mice, we previously observed that it enhanced b-cell proliferation and reduced b-cell death, which reversed T1D (9). Indeed, in various disease models, GABA exerts trophic effects on b-cells and protects against diabetes (9,11). More recent studies reveal that GABA also protects human b-cells against apoptosis and increases their replication rate (12,13).…”

Gamma-aminobutyric acid ameliorates gamma rays-induced oxidative stress in the small intestine of rats

“…It has paracrine and autocrine properties in various peripheral tissues (Watanabe et al, 2002). It has a role in the inhibition of many inflammatory cellular reactions (Tian et al, 2011) and has antidiabetic (Soltani et al, 2011), antioxidant, and free radical-scavenging properties (Deng et al, 2013). GABA is found all over the GI tract, in endocrine-like cells, and in enteric nerves, and it is considered as a neurotransmitter with an endocrine GI tract function (Hyland & Cryan, 2010).…”