Hepatocyte membrane potential regulates serum insulin and insulin sensitivity by altering hepatic GABA release

Abstract

SUMMARY Hepatic lipid accumulation in obesity correlates with the severity of hyperinsulinemia and systemic insulin resistance. Obesity-induced hepatocellular lipid accumulation results in hepatocyte depolarization. We have established that hepatocyte depolarization depresses hepatic afferent vagal nerve firing, increases GABA release from liver slices, and causes hyperinsulinemia. Preventing hepatic GABA release or eliminating the ability of the liver to communicate to the hepatic vagal nerve ameliorates the hyperinsulinemia and insulin resistance associated with diet-induced obesity. In people with obesity, hepatic expression of GABA transporters is associated with glucose infusion and disposal rates during a hyperinsulinemic euglycemic clamp. Single-nucleotide polymorphisms in hepatic GABA re-uptake transporters are associated with an increased incidence of type 2 diabetes mellitus. Herein, we identify GABA as a neuro-hepatokine that is dysregulated in obesity and whose release can be manipulated to mute or exacerbate the glucoregulatory dysfunction common to obesity.

A critical role of hepatic GABA in the metabolic dysfunction and hyperphagia of obesity

“…For example, FGF21 and ANGPTL4 are secreted from hepatocytes in response to liver nutrient flux and can act in an endocrine fashion to impact whole-body metabolism. In line with this, we have recently established that obesity-induced hepatic lipid accumulation increases hepatocyte production and release of the inhibitory neurotransmitter, GABA, in mice (Figure 4A in Geisler et al, 2021 [this issue of Cell Reports ]) that we hypothesize acts in a paracrine fashion to decrease the firing activity of the hepatic vagal afferent nerve (HVAN) to regulate insulin secretion and sensitivity (Figure 5 in Geisler et al, 2021 ). These findings provide a mechanistic link explaining how hepatic lipid accumulation, though increasing extracellular hepatocyte-produced GABA to impair HVAN signaling, drives the development of metabolic diseases.…”

“…In lean mice, which have low hepatic GABA production (Figures 4A and 4B in Geisler et al, 2021 ), there was no effect of EOS or vigabatrin (8 mg/day i.p.) on serum insulin concentrations or insulin sensitivity ( Figures S1I , S1O , and S1P ).…”

“…However, in the liver, GABA-T mediates GABA synthesis ( White, 1981 ). We have proposed that hepatic lipids activate reversed GABA shunt activity in hepatocytes and that hepatic GABA and glucose production are metabolically linked (Figure 5 in Geisler et al, 2021 ). It remains completely untested whether manipulating this GABA shunt can prevent hepatic-steatosis-derived metabolic disease.…”

Study on the Effects of Chinese Materia Medica Processing on the Hypoglycemic Activity and Chemical Composition of Anemarrhenae Rhizoma

“…After the last dose and fasting for 12 hours, take blood from the mouse abdominal aorta, centrifuge, and take serum and plasma; then, take pancreatic tissue, homogenize, and determine glycosylated hemoglobin (HbAlc) [ 12 ], serum resistin (RESISTEIN) [ 13 ], and serum insulin (FINS) [ 14 ] according to the instructions of the enzyme linked immunosorbent assay (ELISA) kit, and calculate the islet sensitivity index (ISI) and insulin resistance index (HOMA-IR) according to the following formulas: ISI = ln[1/(FBG × FINS)]; HOMA-IR = FBG × FINS/22.5 [ 15 ]. Then, determine superoxide dismutase (SOD) [ 16 ], malondialdehyde (MDA) [ 17 ], and nitric oxide (NO) [ 18 ] in pancreatic tissue content.…”

Reduced Liver-Specific PGC1a Increases Susceptibility for Short-Term Diet-Induced Weight Gain in Male Mice

“…Hepatic vagal afferent signaling has been proposed to regulate the efferent vagal control of pancreatic insulin secretion [ 31 , 32 ]. Recently, increased hepatocyte lipid accumulation has been associated with a decreased ATP and membrane depolarization, which was observed to decrease the hepatic vagal afferent signal [ 59 ]. This decrease in the vagal afferent signal appears to be due to the increased hepatocyte secretion of GABA due to decreased Na+/K+-ATPase activity.…”