Highlights
- •Diet-induced NAFLD and associated systemic alterations result in behavioural changes and low-grade brain tissue hypoxia.
- •Brain hypoxia is likely linked to the induced low-grade brain inflammation, as well as cerebrovascular, glial, and metabolic alterations.
- •Mct1 haploinsufficient mice are protected from NAFLD and detrimental cerebral alterations.
- •MCT1 is a potential novel therapeutic target for preventing and/or treating NAFLD and the associated multifactorial encephalopathy.
Background & Aims
Non-alcoholic fatty liver disease (NAFLD) has been associated with mild cerebral dysfunction
and cognitive decline, although the exact pathophysiological mechanism remains ambiguous.
Using a diet-induced model of NAFLD and monocarboxylate transporter-1 (Mct1+/−) haploinsufficient mice, which resist high-fat diet-induced hepatic steatosis, we
investigated the hypothesis that NAFLD leads to an encephalopathy by altering cognition,
behaviour, and cerebral physiology. We also proposed that global MCT1 downregulation
offers cerebral protection.
Methods
Behavioural tests were performed in mice following 16 weeks of control diet (normal
chow) or high-fat diet with high fructose/glucose in water. Tissue oxygenation, cerebrovascular
reactivity, and cerebral blood volume were monitored under anaesthesia by multispectral
optoacoustic tomography and optical fluorescence. Cortical mitochondrial oxygen consumption
and respiratory capacities were measured using ex vivo high-resolution respirometry. Microglial and astrocytic changes were evaluated by
immunofluorescence and 3D reconstructions. Body composition was assessed using EchoMRI,
and liver steatosis was confirmed by histology.
Results
NAFLD concomitant with obesity is associated with anxiety- and depression-related
behaviour. Low-grade brain tissue hypoxia was observed, likely attributed to the low-grade
brain inflammation and decreased cerebral blood volume. It is also accompanied by
microglial and astrocytic morphological and metabolic alterations (higher oxygen consumption),
suggesting the early stages of an obesogenic diet-induced encephalopathy. Mct1 haploinsufficient mice, despite fat accumulation in adipose tissue, were protected
from NAFLD and associated cerebral alterations.
Conclusions
This study provides evidence of compromised brain health in obesity and NAFLD, emphasising
the importance of the liver–brain axis. The protective effect of Mct1 haploinsufficiency points to this protein as a novel therapeutic target for preventing
and/or treating NAFLD and the associated brain dysfunction.
Impact and implications
This study is focused on unravelling the pathophysiological mechanism by which cerebral
dysfunction and cognitive decline occurs during NAFLD and exploring the potential
of monocarboxylate transporter-1 (MCT1) as a novel preventive or therapeutic target.
Our findings point to NAFLD as a serious health risk and its adverse impact on the
brain as a potential global health system and economic burden. These results highlight
the utility of Mct1 transgenic mice as a model for NAFLD and associated brain dysfunction and call for
systematic screening by physicians for early signs of psychological symptoms, and
an awareness by individuals at risk of these potential neurological effects. This
study is expected to bring attention to the need for early diagnosis and treatment
of NAFLD, while having a direct impact on policies worldwide regarding the health
risk associated with NAFLD, and its prevention and treatment.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: August 19, 2022
Accepted:
August 5,
2022
Received in revised form:
July 30,
2022
Received:
November 17,
2021
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