To the Editor:
We read with great interest the spectacular work of Hadjihambi and colleagues, published in August 2022 online ahead of print in the Journal.
[1]
The authors aimed to establish the role of non-alcoholic fatty liver disease (NAFLD) in the development of brain dysfunction. To establish this role, the authors used a mouse model that they generated more than 10 years ago,[2]
monocarboxylate transporter-1 haploinsufficient (Mct1+/−) mice. MCT1 or SLC16A1 is a carrier of short-chain fatty acids, ketone bodies, and lactate in several tissues, including the liver, brain and adipose tissue, playing an important role in energy homeostasis in health and disease, including obesity, type 2 diabetes and cancer. In order to establish the role of NAFLD in diet-induced brain dysfunction, the authors fed mice a high-fat diet (HFD) and added high fructose/glucose to their drinking water. At the end of the dietary period, mice were carefully analysed. The authors observed that HFD resulted in obesity, signs of the metabolic syndrome, NAFLD and signs of brain dysfunction. In contrast, mice haploinsufficient for MCT1 presented with lower body fat, liver fat, insulin and leptin levels, peripheral and central low-grade inflammation, as well as missing signs of obesity-associated encephalopathy. From these data, the authors concluded that their “study provides evidence indicating a key role of NAFLD in inducing low-grade brain tissue hypoxia and inflammation, as well as cerebrovascular, glial, metabolic and behavioural alterations.” While we think that the study is highly interesting, we believe that the conclusion needs further explanation.First, data on the body weight of studied mice is missing in the current report.
[1]
In a previous study from the same authors using the same mouse model fed a pure HFD, marked body weight differences were reported[2]
after the same time period used in the current report. Along these lines, the authors reported that whole body fat mass over the time course of the diet was significantly lower in Mct1+/− mice compared to Mct1+/+ mice. While changes in different fat depots, as well as in the size of adipocytes in subcutaneous adipose tissue, between Mct1+/+ and Mct1+/− mice were reported in previous reports by the authors, these data are not reported in the current paper.[2]
We and others have conclusively shown that differences in body fat content drive low-grade subclinical inflammation in adipose tissue, which the authors speculate to be responsible for diet-induced brain dysfunction. Body fat distribution plays a major role in this regard. Increased visceral adipose tissue mass and dysfunctional subcutaneous adipose tissue are associated with an enhanced subclinical inflammatory response.[3]
Moreover, the ability of the subcutaneous adipose tissue to store lipids is associated with altered fat storage in the liver, as highlighted in partial lipodystrophies or following treatment with thiazolidinediones.[3]
Thus, the presented data do not rule out the option that the brain dysfunction described in Mct1+/+ mice is driven by differences in adipose tissue mass and/or distribution and/or function.The authors reported in their previous work
[2]
that Mct1+/− mice fed a pure HFD have reduced food intake, calorie absorption and enhanced energy expenditure. In the current work, similar food intake between Mct1+/+ and Mct1+/− mice on HFD is reported. Water intake, containing fructose and glucose, is missing. It would be helpful for the reader to understand the diverging results of the previous and the current report. Similarly, energy absorption and energy expenditure are missing. Lower overall caloric intake and/or absorption, resembling caloric restriction, may also account for differences in regional inflammatory responses, NAFLD, and thus, the associated brain dysfunction.[3]
Finally, MCT1 is highly expressed in the brain and the authors previously showed that brain MCT1 expression changes under HFD conditions.
[2]
Moreover, brain MCT1 has been reported to promote microglial activation and a pro-inflammatory effect via 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3.[4]
Thus, it is likely that mice with reduced MCT1 expression will have less brain damage by this mechanism, even without the contribution of the liver. Along these lines, our institution and others have shown that the brain partly controls peripheral glucose and lipid homeostasis, including liver lipid metabolism. The normal insulin-sensitive brain is able to substantially reduce hepatic lipid content upon only one single, central insulin stimulation. The insulin-resistant brain is no longer able to perform this task.[5]
Ectopic lipid accumulation, at least in astrocytes, leads to neuronal insulin resistance.[5]
The authors reported that Mct1+/+ mice had increased brain lipid accumulation.[1]
It is thus tempting to speculate that, in the current report, while the liver might have contributed to brain dysfunction, brain dysfunction could also have preceded and contributed to liver dysfunction.Financial support
The authors received no financial support to produce this manuscript.
Conflict of interest
The authors declare no conflicts of interest that pertain to this work.
Please refer to the accompanying ICMJE disclosure forms for further details.
Authors’ contributions
LS, NE-A and ALB drafted the letter and edited it.
Supplementary data
The following are the supplementary data to this article:
- Multimedia component 1
References
- Partial MCT1 invalidation protects against diet-induced non-alcoholic fatty liver disease and the associated brain dysfunction.J Hepatol. 2023; 78: 180-190
- Resistance to diet-induced obesity and associated metabolic perturbations in haploinsufficient monocarboxylate transporter 1 mice.PloS one. 2013; 8e82505
- Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 Diabetes.Hepatology. 2014; 59: 713-723
- Monocarboxylate transporter 1 promotes classical microglial activation and pro-inflammatory effect via 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3.J Neuroinflammation. 2019; 16: 240
- Central nervous pathways of insulin action in the control of metabolism and food intake.Lancet Diabetes Endocrinol. 2020; 8: 524-534
Article info
Publication history
Published online: October 07, 2022
Accepted:
September 29,
2022
Received:
September 26,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
Author names in bold designate shared co-first authorship
Identification
Copyright
© 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
