Metabolic switching is impaired by aging and facilitated by ketosis independent of glycogen

Hernandez, Abbi R.; Truckenbrod, Leah M.; Federico, Quinten; Campos, Keila T.; Moon, Brianna; Ferekides, Nedi; Hoppe, Meagan; D’Agostino, Dominic P.; Burke, Sara N.

doi:10.18632/aging.103116

Cited by 20 publications

(25 citation statements)

References 86 publications

(132 reference statements)

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“…To induce the state of stable ketosis [ 33 ], we used a high-fat, adequate-protein, low-carbohydrate diet in male Sprague-Dawley rats. As expected, following 3 weeks of a keto-genic diet, (KD)-fed rats ( n = 12) had significantly increased fasting BHB levels (KD: 3.1 ± 0.1 mmol/L vs. Chow: 1.5 ± 0.1 mmol/L, respectively, p < 0.0001, Figure 2 b) but similar fasting blood glucose levels to Chow-fed rats ( n = 15) (KD: 5.1 ± 0.2 mmol/L vs. 5.5 ± 0.3 mmol/L, p = 0.46, Figure 2 a).…”

Section: Resultsmentioning

confidence: 99%

Slow but Steady—The Responsiveness of Sympathoadrenal System to a Hypoglycemic Challenge in Ketogenic Diet-Fed Rats

2021

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The sympathoadrenal counterregulatory response to hypoglycemia is critical for individuals with type 1 diabetes due to impaired ability to produce glucagon. Ketogenic diets (KD) are an increasingly popular diabetes management tool; however, the effects of KD on the sympathoadrenal response are largely unknown. Here, we determined the effects of KD-induced ketosis on the sympathoadrenal response to a single insulin-induced hypoglycemic challenge. We investigated how a 3 week KD feeding regimen affected the main components of the sympathoadrenal counterregulatory response: adrenal sympathetic nerve activity (ASNA), adrenal gland activity, plasma epinephrine, and brainstem glucose-responsive C1 neuronal activation in anesthetized, nondiabetic male Sprague-Dawley rats. Rats on KD had similar blood glucose (BG) levels and elevated ketone body β-hydroxybutyrate (BHB) levels compared to the control Chow diet group. All KD rats responded to hypoglycemia with a robust increase in ASNA, which was initiated at significantly lower BG levels compared to Chow-fed rats. The delay in hypoglycemia-induced ASNA increase was concurrent with rapid disappearance of BHB from cerebral and peripheral circulation. Adrenal gland activity paralleled epinephrine and ASNA response. Overall, KD-induced ketosis was associated with initiation of the sympathoadrenal response at lower blood glucose levels; however, the magnitude of the response was not diminished.

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Section: Resultsmentioning

confidence: 99%

Slow but Steady—The Responsiveness of Sympathoadrenal System to a Hypoglycemic Challenge in Ketogenic Diet-Fed Rats

2021

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“…In this study, despite a long-term ketogenic diet containing only 1% carbohydrates, blood glucose remained at the control level. In some previous studies on ketogenic diets, glucose levels have been reported to be decreased [ 57 , 61 ] but mostly unchanged in the plasma of adult rodents [ 42 , 53 , 62 ]. Some explanation of such effect was published by Leino et al [ 42 ], who performed timeline studies and showed an initial decrease in blood glucose followed by a return to normal levels by 21 days.…”

Section: Discussionmentioning

confidence: 99%

“…Used in this study, young-adult rats have major metabolic flexibility. Hernandez et al [ 61 ] showed that in young rats with a ketogenic diet, glucose levels were higher than in aged rats while they adapted to the ketogenic diet, up to 30 days. It was shown before that induction of hyperketonemia decreased glucose metabolism in 20-day-old rats, but did not alter glucose metabolism in adult rats [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

Increased Beta-Hydroxybutyrate Level Is Not Sufficient for the Neuroprotective Effect of Long-Term Ketogenic Diet in an Animal Model of Early Parkinson’s Disease. Exploration of Brain and Liver Energy Metabolism Markers

Kuter

Olech

Głowacka

et al. 2021

IJMS

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The benefits of a ketogenic diet in childhood epilepsy steered up hope for neuroprotective effects of hyperketonemia in Parkinson’s disease (PD). There are multiple theoretical reasons but very little actual experimental proof or clinical trials. We examined the long-term effects of the ketogenic diet in an animal model of early PD. A progressive, selective dopaminergic medium size lesion was induced by 6-OHDA injection into the medial forebrain bundle. Animals were kept on the stringent ketogenic diet (1% carbohydrates, 8% protein, 70% fat) for 3 weeks prior and 4 weeks after the brain operation. Locomotor activity, neuron count, dopaminergic terminal density, dopamine level, and turnover were analyzed at three time-points post-lesion, up to 4 weeks after the operation. Energy metabolism parameters (glycogen, mitochondrial complex I and IV, lactate, beta-hydroxybutyrate, glucose) were analyzed in the brain and liver or plasma. Protein expression of enzymes essential for gluconeogenesis (PEPCK, G6PC) and glucose utilization (GCK) was analyzed in the liver. Despite long-term hyperketonemia pre- and post-lesion, the ketogenic diet did not protect against 6-OHDA-induced dopaminergic neuron lesions. The ketogenic diet only tended to improve locomotor activity and normalize DA turnover in the striatum. Rats fed 7 weeks in total with a restrictive ketogenic diet maintained normoglycemia, and neither gluconeogenesis nor glycogenolysis in the liver was responsible for this effect. Therefore, potentially, the ketogenic diet could be therapeutically helpful to support the late compensatory mechanisms active via glial cells but does not necessarily act against the oxidative stress-induced parkinsonian neurodegeneration itself. A word of caution is required as the stringent ketogenic diet itself also carries the risk of unwanted side effects, so it is important to study the long-term effects of such treatments. More detailed metabolic long-term studies using unified diet parameters are required, and human vs. animal differences should be taken under consideration.

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“…In animal models, energy consumption patterns can be tightly controlled and optimized to not adversely impact health. The once-daily feeding regime used in the current rat experiments has been shown to improve metabolic function compared to ad libitum feeding, which promotes excessive energy consumption and obesity in rats (Hernandez et al, 2020a ). Thus, food restriction in animals may offer additional experimental control, facilitating investigations into the neurobiological mechanisms of dual-task costs across the lifespan.…”

Section: Discussionmentioning

confidence: 99%

A Cross-species Model of Dual-Task Walking in Young and Older Humans and Rats

Hernandez

Winesett

Federico

et al. 2020

Front. Aging Neurosci.

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Introduction : Dual-task walking is common in daily life but becomes more difficult with aging. Little is known about the neurobiological mechanisms affecting competing cognitive demands. Translational studies with human and animal models are needed to address this gap. This pilot study investigated the feasibility of implementing a novel cross-species dual-task model in humans and rats and aimed to establish preliminary evidence that the model induces a dual-task cost. Methods : Young and older humans and rats performed an object discrimination task (OD), a baseline task of typical walking (baseline), an alternation turning task on a Figure 8 walking course (Alt), and a dual-task combining object discrimination with the alternation task (AltOD). Primary behavioral assessments including walking speed and correct selections for object discrimination and turning direction. In humans, left prefrontal cortex activity was measured with functional near-infrared spectroscopy (fNIRS). Results : Human subjects generally performed well on all tasks, but the older adults exhibited a trend for a slowing of walking speed immediately before the turning decision for Alt and AltOD compared to baseline. Older adults also had heightened prefrontal activity relative to young adults for the Alt and AltOD tasks. Older rodents required more training than young rodents to learn the alternation task. When tested on AltOD with and without a 15-s delay between trials, older rodents exhibited a substantial performance deficit for the delayed version on the initial day of testing. Old rats, however, did not show a significant slowing in walking speed with increasing task demand, as was evident in the young rats. Discussion : This study demonstrates the feasibility and challenges associated with implementing a cross-species dual-task model. While there was preliminary evidence of dual-task cost in both humans and rats, the magnitude of effects was small and not consistent across species. This is likely due to the relative ease of each task in humans and the walking component in rats not being sufficiently challenging. Future versions of this test should make the cognitive tasks more challenging and the motor task in rats more complex.

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Metabolic switching is impaired by aging and facilitated by ketosis independent of glycogen

Cited by 20 publications

References 86 publications

Slow but Steady—The Responsiveness of Sympathoadrenal System to a Hypoglycemic Challenge in Ketogenic Diet-Fed Rats

Slow but Steady—The Responsiveness of Sympathoadrenal System to a Hypoglycemic Challenge in Ketogenic Diet-Fed Rats

Increased Beta-Hydroxybutyrate Level Is Not Sufficient for the Neuroprotective Effect of Long-Term Ketogenic Diet in an Animal Model of Early Parkinson’s Disease. Exploration of Brain and Liver Energy Metabolism Markers

A Cross-species Model of Dual-Task Walking in Young and Older Humans and Rats

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