Distilled database identifies genetic links to rare diseases
24 March 2023
Published online 7 June 2019
Understanding how the neurotransmitter GABA influences the metabolic impact of fat could lead to new treatments for insulin-resistant diabetes.
Adipose tissue, or fat, is an essential organ. Brown fat aids with heat generation, while white fat provides energy reserves and physical protection. But, interestingly, white fat in the abdominal cavity (visceral adipose) is associated with metabolic disorders such as insulin resistance — a precursor to type 2 diabetes — whereas white fat under the skin (subcutaneous adipose) is not. An international research team has now discovered the mechanism behind this difference: the neurotransmitter GABA acts on subcutaneous adipose and deters harmful physiological processes. In the future, a greater understanding of this process may open new doors to combatting insulin resistance in patients.
GABA is essential to normal brain function and is also implicated in some neurological disorders, but its role in other tissues has largely gone unstudied. In their new paper, Seoul National University’s Jae Bum Kim and his team of South Korean, US, and Saudi Arabian researchers has discovered that the activation of GABAB receptors on a subset of subcutaneous fat cells, called adipose-derived stem cells (ADSCs), prevents a potentially pathogenic influx of inflammatory cells and signalling molecules associated with insulin resistance.
Using mice fed on a high-fat diet, the team first searched for differences between visceral and subcutaneous adipose, finding that visceral fat had far higher proinflammatory gene expression and higher influx of inflammatory ‘adipose tissue macrophages’. Similar results were found from tests on samples from obese humans. Further investigation showed a number of genes related to GABA signalling that were expressed differently between visceral and subcutaneous white adipose tissue.
To test the neurotransmitter’s potential role in inflammation-mediated insulin resistance, the team incubated GABA with the two types of fat. Their results showed that GABA-treated subcutaneous fat showed a reduced influx of adipose tissue macrophages, whereas the treatment had no effect on visceral fat. This highlights the specific action of GABA on subcutaneous adipose, which was subsequently narrowed down to the neurotransmitter’s action on ADSCs, a population of cells that the researchers found to be more abundant in subcutaneous fat than visceral.
The researchers also discovered that GABA, injected daily into mice on a high-fat diet, improved blood glucose levels, glucose tolerance scores, and insulin resistance. Insulin signalling improved in subcutaneous fat but not other metabolic organs. Injae Hwang, the study’s first author, says that, taken together, understanding how ADSCs reduce macrophage infiltration and inflammation “may provide the basis to treat obesity-induced insulin resistance,” and could allow scientists the ability to learn how the cells regulate energy metabolism.
“In addition to its role in the central nervous system, our current study elucidates a peripheral role of GABA to confer immunosuppressive characteristics to subcutaneous adipose tissues in obesity,” says Kim. “Our study could address the unsolved question of why and how subcutaneous adipose tissue is metabolically beneficial, unlike visceral adipose tissue.”
Hwang, I. et al. GABA-stimulated adipose-derived stem cells suppress subcutaneous adipose inflammation in obesity. PNAS www.pnas.org/cgi/doi/10.1073/pnas.1822067116 (2019).