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Is NAFLD a key driver of brain dysfunction?

  • Leontine Sandforth
    Affiliations
    German Center for Diabetes Research (DZD e. V.), Neuherberg, Germany

    Institute of Diabetes Research and Metabolic Disease (IDM) of the Helmholtz Center Munich, University of Tübingen, Tübingen, Germany

    Department of Internal Medicine IV, Endocrinology, Diabetology and Nephrology, University Hospital Tübingen, Tübingen, Germany
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  • Nermeen N. El-Agroudy
    Affiliations
    German Center for Diabetes Research (DZD e. V.), Neuherberg, Germany

    Institute of Diabetes Research and Metabolic Disease (IDM) of the Helmholtz Center Munich, University of Tübingen, Tübingen, Germany

    Department of Internal Medicine IV, Endocrinology, Diabetology and Nephrology, University Hospital Tübingen, Tübingen, Germany

    Department of Pharmacology & Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
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  • Andreas L. Birkenfeld
    Correspondence
    Corresponding author. Address: Department of Internal Medicine IV, Endocrinology, Diabetology and Nephrology, University Hospital Tübingen, Otfried Müller Str. 10, 72076 Tübingen, Germany; Tel.: 0049-7071-29-80354, fax 0049-7071-29-80353.
    Affiliations
    German Center for Diabetes Research (DZD e. V.), Neuherberg, Germany

    Institute of Diabetes Research and Metabolic Disease (IDM) of the Helmholtz Center Munich, University of Tübingen, Tübingen, Germany

    Department of Internal Medicine IV, Endocrinology, Diabetology and Nephrology, University Hospital Tübingen, Tübingen, Germany

    School of Cardiovascular and Metabolic Medicine & Sciences, King’s College London, London, UK

    Medizinische Klinik und Poliklinik III, Medizinische Fakultät der Technischen Universität Dresden, Dresden, Germany
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Published:October 07, 2022DOI:https://doi.org/10.1016/j.jhep.2022.09.022

      Linked Article

      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.
      • Hadjihambi A.
      • Konstantinou C.
      • Klohs J.
      • Monsorno K.
      • Le Guennec A.
      • Donnelly C.
      • et al.
      Partial MCT1 invalidation protects against diet-induced non-alcoholic fatty liver disease and the associated brain dysfunction.
      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,
      • Lengacher S.
      • Nehiri-Sitayeb T.
      • Steiner N.
      • Carneiro L.
      • Favrod C.
      • Preitner F.
      • et al.
      Resistance to diet-induced obesity and associated metabolic perturbations in haploinsufficient monocarboxylate transporter 1 mice.
      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.
      • Hadjihambi A.
      • Konstantinou C.
      • Klohs J.
      • Monsorno K.
      • Le Guennec A.
      • Donnelly C.
      • et al.
      Partial MCT1 invalidation protects against diet-induced non-alcoholic fatty liver disease and the associated brain dysfunction.
      In a previous study from the same authors using the same mouse model fed a pure HFD, marked body weight differences were reported
      • Lengacher S.
      • Nehiri-Sitayeb T.
      • Steiner N.
      • Carneiro L.
      • Favrod C.
      • Preitner F.
      • et al.
      Resistance to diet-induced obesity and associated metabolic perturbations in haploinsufficient monocarboxylate transporter 1 mice.
      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.
      • Lengacher S.
      • Nehiri-Sitayeb T.
      • Steiner N.
      • Carneiro L.
      • Favrod C.
      • Preitner F.
      • et al.
      Resistance to diet-induced obesity and associated metabolic perturbations in haploinsufficient monocarboxylate transporter 1 mice.
      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.
      • Birkenfeld A.L.
      • Shulman G.I.
      Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 Diabetes.
      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.
      • Birkenfeld A.L.
      • Shulman G.I.
      Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 Diabetes.
      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
      • Lengacher S.
      • Nehiri-Sitayeb T.
      • Steiner N.
      • Carneiro L.
      • Favrod C.
      • Preitner F.
      • et al.
      Resistance to diet-induced obesity and associated metabolic perturbations in haploinsufficient monocarboxylate transporter 1 mice.
      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.
      • Birkenfeld A.L.
      • Shulman G.I.
      Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 Diabetes.
      Finally, MCT1 is highly expressed in the brain and the authors previously showed that brain MCT1 expression changes under HFD conditions.
      • Lengacher S.
      • Nehiri-Sitayeb T.
      • Steiner N.
      • Carneiro L.
      • Favrod C.
      • Preitner F.
      • et al.
      Resistance to diet-induced obesity and associated metabolic perturbations in haploinsufficient monocarboxylate transporter 1 mice.
      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.
      • Kong L.
      • Wang Z.
      • Liang X.
      • Wang Y.
      • Gao L.
      • Ma C.
      Monocarboxylate transporter 1 promotes classical microglial activation and pro-inflammatory effect via 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3.
      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.
      • Kullmann S.
      • Kleinridders A.
      • Small D.M.
      • Fritsche A.
      • Haring H.U.
      • Preissl H.
      • et al.
      Central nervous pathways of insulin action in the control of metabolism and food intake.
      Ectopic lipid accumulation, at least in astrocytes, leads to neuronal insulin resistance.
      • Kullmann S.
      • Kleinridders A.
      • Small D.M.
      • Fritsche A.
      • Haring H.U.
      • Preissl H.
      • et al.
      Central nervous pathways of insulin action in the control of metabolism and food intake.
      The authors reported that Mct1+/+ mice had increased brain lipid accumulation.
      • Hadjihambi A.
      • Konstantinou C.
      • Klohs J.
      • Monsorno K.
      • Le Guennec A.
      • Donnelly C.
      • et al.
      Partial MCT1 invalidation protects against diet-induced non-alcoholic fatty liver disease and the associated brain dysfunction.
      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:

      References

        • Hadjihambi A.
        • Konstantinou C.
        • Klohs J.
        • Monsorno K.
        • Le Guennec A.
        • Donnelly C.
        • et al.
        Partial MCT1 invalidation protects against diet-induced non-alcoholic fatty liver disease and the associated brain dysfunction.
        J Hepatol. 2023; 78: 180-190
        • Lengacher S.
        • Nehiri-Sitayeb T.
        • Steiner N.
        • Carneiro L.
        • Favrod C.
        • Preitner F.
        • et al.
        Resistance to diet-induced obesity and associated metabolic perturbations in haploinsufficient monocarboxylate transporter 1 mice.
        PloS one. 2013; 8e82505
        • Birkenfeld A.L.
        • Shulman G.I.
        Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 Diabetes.
        Hepatology. 2014; 59: 713-723
        • Kong L.
        • Wang Z.
        • Liang X.
        • Wang Y.
        • Gao L.
        • Ma C.
        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
        • Kullmann S.
        • Kleinridders A.
        • Small D.M.
        • Fritsche A.
        • Haring H.U.
        • Preissl H.
        • et al.
        Central nervous pathways of insulin action in the control of metabolism and food intake.
        Lancet Diabetes Endocrinol. 2020; 8: 524-534