Study finds key gene deletion shields mice from diet-induced obesity and liver disease

By Dr. Priyom Bose, Ph.D.Reviewed by Benedette Cuffari, M.Sc.Dec 13 2023

A recent International Journal of Obesity study explores the role of brain and muscle aryl hydrocarbon receptor nuclear translocator-like1 (BMAL1) in the development of non-alcoholic fatty liver disease (NAFLD) and obesity.

Study: BMAL1 deletion protects against obesity and non-alcoholic fatty liver disease induced by a high-fat diet. Image Credit: Jo Panuwat D / Shtuterstock.com

Background

The prevalence of obesity has significantly increased and, as a result, remains a major global public health issue. Several studies have shown that obesity is linked with the manifestations of many complications, such as NAFLD, hypertension, osteoarthritis, and diabetes. 

NAFLD is a common chronic liver disease with a rising global prevalence. Although several genetic, metabolic, and microbial factors linked to this disease have been identified, its precise pathogenesis remains elusive.

NAFLD is a progressive disease that could result in non-alcoholic steatohepatitis, hepatocellular carcinoma, cirrhosis, or non-alcoholic hepatic steatosis with or without mild inflammation. Patients with NAFLD experience ectopic lipid deposition and fat pool expansion due to overnutrition.

A pro-inflammatory environment in NAFLD is created due to macrophage infiltration into visceral adipose tissue, which induces insulin resistance. This causes de novo lipogenesis and increased lipolysis in the adipose tissue in the liver.

Unbalanced lipid metabolism results in the significant accumulation of lipids in the liver, which could lead to cellular oxidative stress, apoptosis, and inflammasome activation. These conditions increase the risk of liver inflammation, fiber deposition, and tissue regeneration.

Two of the most critical drivers of NAFLD are circadian rhythms and a complex neuroendocrine system associated with lipid metabolism. A disruption in circadian rhythm could unbalance physiological functions and promote the manifestation of obesity and NAFLD. 

Previous studies have shown that circadian rhythms in mammals are regulated by the transcription-translation feedback loop system, which contains multiple circadian genes. Some of the identified circadian genes include BMAL1, cryptochrome circadian regulator 1 (i.e., CRY1), RAR-related orphan receptor A (RORA), circadian locomotor output cycles kaput (CLOCK), and period circadian regulator 1 and 2 (i.e., PER1 and PER2, respectively).

BMAL1 and CLOCK are positively associated with driving the circadian cycle through a transcription-translation feedback loop. Although BMAL1 has been linked to the manifestation of high-fat diet (HFD)-induced obesity, its precise role in this condition is not known.

About the study

The current study determined the role of BMAL1 in the pathogenesis of NAFLD and obesity. BMAL1 knockout (KO) mice and wild-type (WT) mice-control were used for experimental purposes. A total of six BMAL1 KO mice were fed with 60% HFD, five WT mice were fed normal chow (NC), and the other five WT mice were fed HFD for twenty weeks.

Before sample collection, all mice were fasted for twelve hours. After twenty weeks, the test mice underwent an intraperitoneal glucose tolerance test (IPGTT) and an intraperitoneal insulin tolerance test (IPITT). Before administration of 0.75 U/kg intraperitoneal insulin, mice were fasted for four hours.

Study findings

The current study stimulated the circadian rhythm in mice by deleting BMAL1 genes, which allowed the researchers to study its role in the development of metabolic disorders and obesity. At week zero, the normal expression of BMAL1 was observed in the livers of WT mice.

After four weeks of intervention, WT mice fed with either NC or HFD gained weight in a time-dependent manner. Weight gain continued in the WT + HFD group until the end of the experiment at 20 weeks.

Although the weight of BMAL1 KO mice at baseline was lower than WT mice, it increased during the first weeks of HFD and became similar to that of the WT + HFD group. After six weeks, the increase in weight became stabilized in the BMAL1 KO + HFD group, which eventually became lower than in the WT + HFD group. 

The experimental results imply that BMAL1 deletion protects against HFD-induced obesity and metabolic disorders. Moreover, it is evident that BMAL1 negatively impacts metabolism and plays a crucial role in HFD-induced obesity and metabolic diseases, including NAFLD.

Mechanistically, BMAL1 KO suppressed CD36 and PPARγ expression in the liver. Previous studies have shown that this gene is responsible for the liver fatty acid uptake gene.

Conclusions

The experimental findings of the current study support that BMAL1 is an important component of the molecular clock. This gene is closely associated with the manifestations of obesity and metabolic diseases.

The current study observed that BMAL1 depletion prevents lipid deposition and hepatic fatty acid uptake by inhibiting the hepatic PPARγ-CD36 pathway. Therefore, BMAL1 could be targeted to treat obesity and NAFLD.