Role of hepatic GABA in obesity-related hyperphagia

Akash Singh, Banaras Hindu University

Thirty million Americans have type 2 diabetes (T2D), while another 81 million have pre-diabetes. As a result, diabetes affects 46% of the adult population in the United States, making it the seventh greatest cause of mortality in the country and accounting for one out of every seven dollars spent on health care. Even within the Indian subcontinent, recent trends indicate that the prevalence of diabetes is increasing at an alarming rate. Diabetes was found to be more prevalent in the southern part of India, with a prevalence of 13.5% among Chennai residents, 12.4% in Bangalore, and 16.6% in Hyderabad, compared to eastern India’s 11.7% (Kolkata), northern India’s 11.6% (New Delhi), and western India’s 9.3% (Mumbai). A group of researchers from the University of Arizona has observed the role of hepatic GABA in obesity-related hyperphagia, and that increased hepatic GABA production leads to a variety of metabolic disorders, including Type 2 diabetes.

Type 2 Diabetes:

Type 2 diabetes is also called non-insulin-dependent diabetes. In this case, your pancreas generally produces insulin. However, either it is insufficient or your body does not utilize it properly. Insulin resistance is seen in those who have type 2 diabetes.

Hallmarks of Type 2 Diabetes (T2D):

Hepatic steatosis is a defining feature of T2D, as hepatic lipid accumulation is directly linked to the severity of peripheral insulin resistance and hyperinsulinemia. Furthermore, diabetes affects 87% of the population, with 87% of diabetics being overweight or obese. Obesity and T2D are also marked by a disruption in energy balance, specifically a reduction in meal-induced satiety, which can lead to excessive energy consumption.

GABA (Gamma-Aminobutyric acid):

In the developed mammalian central nervous system, it is the primary inhibitory neurotransmitter. Its main function is to reduce neuronal excitability across the nervous system. GABAergic neurons are neurons that produce GABA as an output.

GABA is produced in relatively high quantities in the insulin-producing -cells of the pancreas, in addition to the neurological system. GABA is secreted alongside insulin by the -cells and the GABA binds to GABA receptors on nearby islet -cells, preventing them from secreting glucagon (which would negate insulin’s actions).

Role of hepatic GABA in obesity-related hyperphagia:

Obesity-induced hyperinsulinemia, insulin resistance, and hyperphagia, according to the researchers, maybe fueled by hepatic lipid buildup. In reaction to acute and chronic nutritional status, the liver generates and releases hepatokines into the bloodstream. Obesity-induced hepatic lipid accumulation increases hepatocyte production and release of the inhibitory neurotransmitter GABA, which operates in a paracrine manner to reduce the firing activity of the hepatic vagal afferent nerve (HVAN), which regulates insulin secretion and sensitivity in mice.

A tricarboxylic acid cycle detour that converts a-ketoglutarate to succinate while also breaking down a molecule of GABA via GABA-transaminase is known as the GABA shunt (GABA-T). GABA-T, on the other hand, mediates GABA production in the liver. By decreasing hepatic GABA synthesis, GABA-T represents a prospective target for lowering hyperinsulinemia and insulin resistance.

Models proposed to limit hepatic GABA production:

1. Pharmacologic inhibition of GABA-T activity: GABA-T inhibitors such as ethanolamine-O-sulfate (EOS) or vigabatrin (8 mg/day intraperitoneally [i.p.]) were used, and both lowered hepatic GABA-T activity by over 90% in just two days. In comparison to pre-treatment, 4 days of EOS or vigabatrin administration lowered blood insulin and glucose concentrations and increased the glucose: insulin ratio. After a 2-week washout from EOS or vigabatrin, blood insulin, and the glucose: insulin ratio returned to pretreatment values. Within four days of starting treatment, both GABA-T inhibitors enhanced insulin sensitivity as measured by the insulin tolerance test (ITT).
2. Antisense oligonucleotide (ASO)-mediated knockdown of hepatic-specific GABA-T expression: ASOs given peripherally do not cross the blood-brain barrier. Within one week, a GABA-T targeted ASO (12.5 mg/kg i.p. twice weekly) reduced hepatic GABA-T mRNA expression by >98%. Obesity-induced liver slice GABA release was reduced by 61% when GABA-T was knocked out. Oral glucose clearance was enhanced by GABA-T-targeted ASO injections without influencing oral glucose-stimulated serum insulin concentrations.

Conclusion:

Obese people generally have a hard time losing weight and keeping it off. The efficiency of weight loss techniques is likely to be harmed by dysregulated satiety signals. This research highlights hepatic GABA synthesis as a potential therapeutic target for obesity, as it improves systemic glucose homeostasis while also lowering food consumption. Hepatic GABA synthesis and transport are linked to glucoregulatory indicators, T2D, and BMI in obese people, suggesting that this research could be used to improve metabolic health in humans.

Also read: Every Mutation is Detrimental

Reference:

1. Geisler, C.E., Ghimire, S., Bruggink, S.M., et al. (2021). A critical role of hepatic GABA in the metabolic dysfunction and hyperphagia of obesity. Cell Reports, 35(13). https://doi.org/10.1016/j.celrep.2021.109301

About author:

Akash Singh is a first year masters student of Biochemistry in Banaras Hindu University. He plans to pursue a PhD in future. He aims to pursue his career in research and teach the young minds of the country.

Social media links : LinkedIn : https://www.linkedin.com/in/akash-singh-82b5811a2/

Publications :

1. https://vidwaanforever.com/2021/06/a-new-period-invention-a-novel-thread-device-for-uti-detection/
2. https://vidwaanforever.com/2021/06/the-fall-of-insecta-apocalyptic-consequences-for-humanitys-survival/

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