The impact of ageing, fasting and high‐fat diet on central and peripheral glucose tolerance and glucose‐sensing neural networks in the arcuate nucleus

Top, M. van den; Zhao, Fengshu; Viriyapong, R.; Michael, Natalie J.; Munder, Astrid C; Pryor, Jack T.; Renaud, Leo P.; Spanswick, David

doi:10.1111/jne.12528

Cited by 8 publications

(4 citation statements)

References 114 publications

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“…These data do contradict previous studies that showed no alterations in hippocampus metabolic profiles, particularly in genetically modified obese rats [73]. Male Wistar-Han rats fed a 40% HFD for 20 weeks demonstrated reductions in glucose tolerance in both plasma and cerebrospinal fluid following glucose challenge, suggesting that HFD induced changes in both central and peripheral glucose tolerance [68] (Table 4).…”

Section: Braincontrasting

confidence: 92%

High Fat Rodent Models of Type 2 Diabetes: From Rodent to Human

Stott

Marino

2020

Nutrients

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Poor dietary habits contribute to increased incidences of obesity and related co-morbidities, such as type 2 diabetes (T2D). The biological, genetic, and pathological implications of T2D, are commonly investigated using animal models induced by a dietary intervention. In spite of significant research contributions, animal models have limitations regarding the translation to human pathology, which leads to questioning their clinical relevance. Important considerations include diet-specific effects on whole organism energy balance and glucose and insulin homeostasis, as well as tissue-specific changes in insulin and glucose tolerance. This review will examine the T2D-like phenotype in rodents resulting from common diet-induced models and their relevance to the human disease state. Emphasis will be placed on the disparity in percentages and type of dietary fat, the duration of intervention, and whole organism and tissue-specific changes in rodents. An evaluation of these models will help to identify a diet-induced rodent model with the greatest clinical relevance to the human T2D pathology. We propose that a 45% high-fat diet composed of approximately one-third saturated fats and two-thirds unsaturated fats may provide a diet composition that aligns closely to average Western diet macronutrient composition, and induces metabolic alterations mirrored by clinical populations.

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Section: Braincontrasting

confidence: 92%

High Fat Rodent Models of Type 2 Diabetes: From Rodent to Human

Stott

Marino

2020

Nutrients

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“…To show impaired glucose-sensing in AgRP neurons, we recorded neuronal responses to an increase in extracellular glucose from a basal level of 2 mM to 5 mM. These glucose concentrations were chosen to represent brain glucose concentrations under fasting and fed conditions, based on estimates in the CSF from fasted and fed rats and mice ( van den Top et al, 2017 ). Glucose-excited neurons were defined based upon a response characterised by membrane potential depolarisation and/or an increase in action potential firing frequency with increased extracellular glucose ( Figure 1—figure supplement 1B ).…”

Section: Resultsmentioning

confidence: 99%

Metabolic sensing in AgRP neurons integrates homeostatic state with dopamine signalling in the striatum

Reichenbach

Clarke

Stark

et al. 2022

eLife

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Agouti-related peptide (AgRP) neurons increase motivation for food, however whether metabolic sensing of homeostatic state in AgRP neurons potentiates motivation by interacting with dopamine reward systems is unexplored. As a model of impaired metabolic-sensing, we used the AgRP-specific deletion of carnitine acetyltransferase (Crat) in mice. We hypothesized that metabolic sensing in AgRP neurons is required to increase motivation for food reward by modulating accumbal or striatal dopamine release. Studies confirmed that Crat deletion in AgRP neurons (KO) impaired ex vivo glucose-sensing, as well as in vivo responses to peripheral glucose injection or repeated palatable food presentation and consumption. Impaired metabolic-sensing in AgPP neurons reduced acute dopamine release (seconds) to palatable food consumption and during operant responding, as assessed by GRAB-DA photometry in the nucleus accumbens, but not the dorsal striatum. Impaired metabolic-sensing in AgRP neurons suppressed radiolabelled 18F-fDOPA accumulation after ~30 minutes in the dorsal striatum but not the nucleus accumbens. Impaired metabolic sensing in AgRP neurons suppressed motivated operant responding for sucrose rewards during fasting. Thus, metabolic-sensing in AgRP neurons is required for the appropriate temporal integration and transmission of homeostatic hunger-sensing to dopamine signalling in the striatum.

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“…Another established outcome of DIO is dysregulation of glucose homeostasis [ 70 , 71 ]. We first examined changes in fasting glucose levels over the treatment period.…”

Section: Resultsmentioning

confidence: 99%

TLR4 inhibitor TAK-242 attenuates the adverse neural effects of diet-induced obesity

Moser

Uchoa

Pike

2018

J Neuroinflammation

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BackgroundObesity exerts negative effects on brain health, including decreased neurogenesis, impaired learning and memory, and increased risk for Alzheimer’s disease and related dementias. Because obesity promotes glial activation, chronic neuroinflammation, and neural injury, microglia are implicated in the deleterious effects of obesity. One pathway that is particularly important in mediating the effects of obesity in peripheral tissues is toll-like receptor 4 (TLR4) signaling. The potential contribution of TLR4 pathways in mediating adverse neural outcomes of obesity has not been well addressed. To investigate this possibility, we examined how pharmacological inhibition of TLR4 affects the peripheral and neural outcomes of diet-induced obesity.MethodsMale C57BL6/J mice were maintained on either a control or high-fat diet for 12 weeks in the presence or absence of the specific TLR4 signaling inhibitor TAK-242. Outcomes examined included metabolic indices, a range of behavioral assessments, microglial activation, systemic and neuroinflammation, and neural health endpoints.ResultsPeripherally, TAK-242 treatment was associated with partial inhibition of inflammation in the adipose tissue but exerted no significant effects on body weight, adiposity, and a range of metabolic measures. In the brain, obese mice treated with TAK-242 exhibited a significant reduction in microglial activation, improved levels of neurogenesis, and inhibition of Alzheimer-related amyloidogenic pathways. High-fat diet and TAK-242 were associated with only very modest effects on a range of behavioral measures.ConclusionsThese results demonstrate a significant protective effect of TLR4 inhibition on neural consequences of obesity, findings that further define the role of microglia in obesity-mediated outcomes and identify a strategy for improving brain health in obese individuals.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1340-0) contains supplementary material, which is available to authorized users.

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The impact of ageing, fasting and high‐fat diet on central and peripheral glucose tolerance and glucose‐sensing neural networks in the arcuate nucleus

Cited by 8 publications

References 114 publications

High Fat Rodent Models of Type 2 Diabetes: From Rodent to Human

High Fat Rodent Models of Type 2 Diabetes: From Rodent to Human

Metabolic sensing in AgRP neurons integrates homeostatic state with dopamine signalling in the striatum

TLR4 inhibitor TAK-242 attenuates the adverse neural effects of diet-induced obesity

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