Research title: 

Antisense oligonucleotides of methionine adenosyltransferase 1a activate the liver-brown adipose tissue axis, preventing obesity and associated hepatosteatosis.

Journal:

Nature Communications.

Access: 

https://addi.ehu.es/bitstream/handle/10810/57907/s41467-022-28749-z.pdf?sequence=1&isAllowed=y 

Introduction:

The rise in obesity has led to an increase in metabolic diseases such as type 2 diabetes, dyslipidemia, and non-alcoholic fatty liver disease (NAFLD). The latter is the leading cause of chronic liver disease in Western countries, ranging from fat accumulation in the liver (hepatosteatosis) to a more advanced form called non-alcoholic steatohepatitis (NASH). Although there are no specific pharmacological treatments for NAFLD, treatments affecting body weight and glucose control have been investigated because obesity is a significant risk factor.

In obese patients, where NAFLD is common, elevated levels of S-adenosylmethionine (SAMe) are found in serum, related to abdominal adiposity and higher caloric intake, suggesting increased hepatic synthesis of SAMe. SAMe is produced in the first stage of the methionine cycle through the action of methionine adenosyltransferase (MAT). The development of obesity is linked to high methionine intake, which increases SAMe levels. Dietary methionine restriction has been shown to reduce adiposity and improve insulin sensitivity.

The lack of certain enzymes involved in the methionine cycle in mice confers resistance to obesity and related diseases. Furthermore, chronic changes in hepatic SAMe levels are associated with the development of NAFLD with age. Maintaining normal SAMe levels is crucial for proper liver function during aging. The impact of pharmacological suppression of the Mat1a gene, which participates in the methionine cycle, on obesity and obesity-related NAFLD was investigated.

The role of ratecholamines in this article:

Catecholamines, such as adrenaline and noradrenaline, play a crucial role in regulating energy metabolism and adipose tissue function in the context of obesity and non-alcoholic fatty liver disease (NAFLD). These neurotransmitter hormones stimulate lipolysis, the process by which stored fats in adipose tissue are broken down into fatty acids and released for energy utilization. Additionally, catecholamines promote thermogenesis in brown adipose tissue (BAT), a specialized type of adipose tissue that has the unique ability to generate heat in response to stimuli such as cold and sympathetic nervous system activation. BAT thermogenesis contributes to energy balance regulation by burning fats and generating heat, which helps maintain body temperature and basal metabolism.

The mentioned article investigates how suppression of the Mat1a gene, involved in the methionine cycle, may have beneficial effects on brown adipose tissue metabolism and function, possibly through modulation of catecholamines and their role in thermogenesis. By understanding how catecholamines and BAT are affected in the context of obesity and NAFLD, new therapeutic strategies can be identified to address these metabolic conditions.

ELISA FOR THE DETECTION OF CATECHOLAMINES:

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Using the ELISA KIT, epinephrine and norepinephrine could be measured in serum and BAT of mice fed a high-fat diet (HFD) treated with Mat1a ASO and control ASO. Changes in hepatic Mat1a did not produce changes in serum catecholamine levels. However, the concentration of catecholamines per gram of BAT decreased when targeting hepatic Mat1a.

Conclusion:

The most significant finding in the text is that inhibition of the Mat1a gene reverses and prevents obesity, insulin resistance, and associated hepatosteatosis by reducing serum lipids. It is demonstrated that Mat1a deficiency has beneficial effects on brown adipose tissue (BAT) metabolism and function, as well as on liver lipid synthesis. Additionally, it is observed that Mat1a suppression induces thermogenesis in BAT and secretion of FGF21, a hormone with potential therapeutic effects in obesity and associated metabolic diseases. This finding suggests that Mat1a inhibition could be a promising strategy for the treatment of obesity and its metabolic complications.

These results were published in Nature Communications on March 1, 2022.

https://addi.ehu.es/bitstream/handle/10810/57907/s41467-022-28749-z.pdf?sequence=1&isAllowed=y 

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