Correlation between ketones and mental fatigue in high fat‐induced obese and non‐obese rats

Niepoetter, Paige; Butts-Wilmsmeyer, Carrie J.; Kaviani, Sepideh; Viernow, Coral; Ruholl, Hannah; Gopalan, C.

doi:10.14814/phy2.14930

Cited by 7 publications

(9 citation statements)

References 27 publications

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“…The NOR test is used as a measure of short-term episodic memory, and we have previously used this test to show acute i.c.v administration of soluble amyloid β oligomers caused robust and enduring deficits ( Watremez et al, 2018 ). In line with the published literature, we found that 4 weeks of high-fat feeding results in cognitive impairment in Sprague Dawley rats ( Niepoetter et al, 2021 ). Hence, we injected the shRNA construct targeting CMKLR1 into rats after 4 weeks of high-fat feeding.…”

Section: Discussionsupporting

confidence: 92%

The Chemerin-CMKLR1 Axis is Functionally important for Central Regulation of Energy Homeostasis

et al. 2022

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Chemerin is an adipokine involved in inflammation, adipogenesis, angiogenesis and energy metabolism, and has been hypothesized as a link between obesity and type II diabetes. In humans affected by obesity, chemerin gene expression in peripheral tissues and circulating levels are elevated. In mice, plasma levels of chemerin are upregulated by high-fat feeding and gain and loss of function studies show an association of chemerin with body weight, food intake and glucose homeostasis. Therefore, chemerin is an important blood-borne mediator that, amongst its other functions, controls appetite and body weight. Almost all studies of chemerin to date have focused on its release from adipose tissue and its effects on peripheral tissues with the central effects largely overlooked. To demonstrate a central role of chemerin, we manipulated chemerin signaling in the hypothalamus, a brain region associated with appetite regulation, using pharmacological and genetic manipulation approaches. Firstly, the selective chemerin receptor CMKLR1 antagonist α-NETA was administered i.c.v. to rats to test for an acute physiological effect. Secondly, we designed a short-hairpin-RNA (shRNA) lentivirus construct targeting expression of CMKLR1. This shRNA construct, or a control construct was injected bilaterally into the arcuate nucleus of male Sprague Dawley rats on high-fat diet (45%). After surgery, rats were maintained on high-fat diet for 2 weeks and then switched to chow diet for a further 2 weeks. We found a significant weight loss acutely and inhibition of weight gain chronically. This difference became apparent after diet switch in arcuate nucleus-CMKLR1 knockdown rats. This was not accompanied by a difference in blood glucose levels. Interestingly, appetite-regulating neuropeptides remained unaltered, however, we found a significant reduction of the inflammatory marker TNF-α suggesting reduced expression of CMKLR1 protects from high-fat diet induced neuroinflammation. In white and brown adipose tissue, mRNA expression of chemerin, its receptors and markers of adipogenesis, lipogenesis and brown adipocyte activation remained unchanged confirming that the effects are driven by the brain. Our behavioral analyses suggest that knockdown of CMKLR1 had an impact on object recognition. Our data demonstrate that CMKLR1 is functionally important for the central effects of chemerin on body weight regulation and neuroinflammation.

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Section: Discussionsupporting

confidence: 92%

The Chemerin-CMKLR1 Axis is Functionally important for Central Regulation of Energy Homeostasis

et al. 2022

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“…ANOVA of individual variables. Measurements of body weight, blood glucose and ketones as well as the behavioral data analysis during DIO is previously published [34]. In this study, body weight, blood glucose, and blood ketones were measured once per week and the averages of each of these variables analyzed using a repeated measures analysis of variance (ANOVA) in PROC MIXED of SAS (version 9.4).…”

Section: Discussionmentioning

confidence: 99%

“…The remaining IEIs occurred at 24-hours (one day), 72 hours (3 days), and 168-hours (7 days) after the initial 0-hour test. The duration spent by the rats investigating the new object compared to the familiar object translates to the animal’s recognition and provides a numerical measurement for memory [ 34 , 42 ].…”

Section: Methodsmentioning

confidence: 99%

“…A study by Murray et al (2016) found improved memory during radial arm maze testing in rats fed a high ketone ester diet which resulted in higher plasma beta-hydroxybutyrate levels after 36 days of this dietary intervention [ 24 ]. Our previous study using HFD-induced obese rats had increased ketone levels which were associated with greater time spent with novel versus familiar objects in NOR testing, indicating that ketones protected against memory deficits [ 34 ]. Ketones may exert these benefits in a number of ways.…”

Section: Introductionmentioning

confidence: 99%

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Intermittent fasting and mental and physical fatigue in obese and non-obese rats

Niepoetter

Butts-Wilmsmeyer²,

Gopalan³

2022

PLoS ONE

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Intermittent fasting (IF) is an alternating pattern of restricting eating. This study evaluated mental and physical fatigue secondary to IF (daily 18-hour fast, 7-days-a-week) in the high-fat diet (HFD)-induced male obese Sprague Dawley rats. Fifty-four rats were randomly assigned to a HFD (n = 28) or a standard diet (SD; n = 26). After six weeks, the HFD rats were divided into one of four groups: obese HFD ad libitum (OB-HFD-AL), obese HFD-IF (OB-HFD-IF), obese SD-AL (OB-SD-AL), and obese SD-IF (OB-SD-IF). Similarly, non-obese controls were grouped into HFD-AL (C-HFD-AL), non-obese HFD-IF (C-HFD-IF), non-obese SD-AL (C-SD-AL), and non-obese SD-IF (C-SD-IF). After 2 weeks of IF, mental and physical fatigue were measured using open field (OF) and novel object recognition (NOR) tests. Rats on IF gained weight at a slower pace (p<0.05) and had lower glucose levels (p<0.01) compared to the AL group. In non-obese rats, ketone levels were higher in the IF-HFD group than IF-SD (p<0.05) and AL-SD (p<0.01) animals. Obese rats exhibited elevated blood ketone levels in IF-SD conditions versus AL-SD rats (p<0.01). AL-HFD rats had higher ketone levels than AL-SD animals in both obese and non-obese groups (p<0.05). In conclusion, rats with higher blood ketone levels, whether they were on IF or AL, traveled a greater distance during OF suggesting a lack of physical fatigue. There was no significant difference between IF and AL during NOR indicating a lack of mental fatigue. Thus, IF results in reduced body weight and blood glucose levels but does not induce physical or mental fatigue.

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“…The recent proof indicates a linear relationship between obesity and cognitive deficits, and an increased risk of dementia and Alzheimer's disease (AD) later in life as well (Solas et al, 2017). Studies in animal models of obesity have shown that SD rats exhibit impaired learning and cognitive function with decreased neuronal and myelin viability after high-fat dietary feeding (Niepoetter et al, 2021). Previous literature has reported that the development of obesity-related cognitive impairment may be associated with inflammation, insulin resistance, disruption of the blood-brain barrier, and abnormal endocrine function, but more precise mechanisms need to be researched (Solas et al, 2017;Niepoetter et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Effect of semaglutide and empagliflozin on cognitive function and hippocampal phosphoproteomic in obese mice

Chen

et al. 2023

Front. Pharmacol.

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Objective: Based on the 4D label-free phosphoproteomic technique, we examined the differences in cognitive function and hippocampal phosphorylated protein expression in high-fat diet-induced obese mice after the intervention of semaglutide and empagliflozin, as well as the effects of both on protein activity and function in obese mice’s hippocampal tissues and the signaling pathways involved.Methods: Thirty-two C57BL/6JC male mice were assigned to two groups randomly: A control group (group C, 10% of energy is from fat, n = 8) and a high-fat diet group (group H, 60% of energy is from fat, n = 24). The high-fat diet-induced obese mice were screened after 12 weeks of feeding based on the criterion that the bodyweight of mice in fat rich diet group was greater than or equal to 20% of the average body weight of the mice in the blank control group. Group H separate into group H (n = 8), group Semaglutide (group S, n = 8), and group empagliflozin (group E, n = 8). For a total of 12 weeks, group S received 30 nmol/kg/d bodyweight of semaglutide intraperitoneally, group E received 10 mg/kg/d bodyweight of empagliflozin via gavage, and groups C and H received equal amounts of saline by intraperitoneal injection and gavage. At the end of treatment, the mice were appraised for cognitive function employing the Morris water maze (MWM), and serum fasting glucose, lipids, and inflammatory parameters were measured. The 4D label-free phosphoproteomics method was employed to screen the differential phosphoproteins and loci in hippocampal tissues of mice in different treatment groups, and bioinformatics was used to analyze the biological processes, signaling pathways, and related protein–protein interaction (PPI) network analysis of these differentially phosphorylated proteins.Results: In comparison to normal controls, The escape latency of obese mice induced by high-fat diet was prolonged, the percentage of swimming time in the target quadrant was reduced, and the number of times of crossing the platform was reduced, whereas semaglutide and empagliflozin treatment reduced escape latency, increase the percentage of swim time in the target quadrant and increase the frequency of passing through the platform area, although there is little difference in the effect of the two drugs. The phosphoproteomic results showed 20,493 unique phosphorylated peptides, representing 21,239 phosphorylation sites and 4,290 phosphorylated proteins. Further analysis revealed that the proteins corresponding to these differentially phosphorylated sites are jointly distributed in signaling pathways such as dopaminergic synapses and axon guidance, and are involved in biological processes such as neuronal projection development, synaptic plasticity, and axonogenesis. Notably, the key factors voltage-dependent L-type calcium channel subunit alpha-1D (CACNA1D), voltage-dependent P/Q-type calcium channel subunit alpha-1A (CACNA1A), and voltage-dependent N-type calcium channel subunit alpha-1B (CACNA1B) were all found to be involved in the dopaminergic synapse pathway, and their expression was upregulated by semaglutide and empagliflozin.Conclusion: We found for the first time that a high-fat diet decreased CACNA1D, CACNA1A, and CACNA1B protein serine phosphorylation, which may affect neuronal development, synaptic plasticity, and cognitive function in mice. Notably, semaglutide and empagliflozin increased the phosphorylation of these proteins.

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Correlation between ketones and mental fatigue in high fat‐induced obese and non‐obese rats

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 7 publications

References 27 publications

The Chemerin-CMKLR1 Axis is Functionally important for Central Regulation of Energy Homeostasis

The Chemerin-CMKLR1 Axis is Functionally important for Central Regulation of Energy Homeostasis

Intermittent fasting and mental and physical fatigue in obese and non-obese rats

Effect of semaglutide and empagliflozin on cognitive function and hippocampal phosphoproteomic in obese mice

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