Insights in the regulation of trimetylamine N-oxide production using a comparative biomimetic approach suggest a metabolic switch in hibernating bears

Ebert, Thomas; Painer, Johanna; Bergman, Peter; Qureshi, Abdul Rashid; Giroud, Sylvain; Stalder, Gabrielle; Kublickiene, Karolina; Göritz, Frank; Vetter, Sebastian; Bieber, Claudia; Fröbert, Ole; Arnemo, Jon M.; Zedrosser, Andreas; Redtenbacher, Irene; Shiels, Paul G.; Johnson, Richard J.; Stenvinkel, Peter

doi:10.1038/s41598-020-76346-1

Cited by 23 publications

(19 citation statements)

References 101 publications

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“…Hibernators have been described to have developed natural resistance to chronic kidney disease (CKD), often associated with cardiovascular impairments in humans (for reviews, see Romagnani et al, 2017 ; Sarnak et al, 2019 ), despite their long hibernation fast during winter. Indeed, it was recently reported that markers of CKD differed significantly between animal species with different feeding habits and thermoregulatory behaviors, and that hibernating brown bears and garden dormice displayed higher levels of betaine and choline (known to be cardioprotective) and lower, sometimes even non-detectable, levels of trimethylamine N-oxide (TMAO), a marker of CDK in human and animals ( Ebert et al, 2020 ). Hence, the betaine endogenously produced by the organism may protect organs (notably kidney) of bears, dormice, and other hibernators from oxidative or other damages during the hibernation period of depressed metabolism.…”

Section: Protective Mechanisms During the State Of Metabolic Depressimentioning

confidence: 99%

The Torpid State: Recent Advances in Metabolic Adaptations and Protective Mechanisms†

et al. 2021

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Torpor and hibernation are powerful strategies enabling animals to survive periods of low resource availability. The state of torpor results from an active and drastic reduction of an individual’s metabolic rate (MR) associated with a relatively pronounced decrease in body temperature. To date, several forms of torpor have been described in all three mammalian subclasses, i.e., monotremes, marsupials, and placentals, as well as in a few avian orders. This review highlights some of the characteristics, from the whole organism down to cellular and molecular aspects, associated with the torpor phenotype. The first part of this review focuses on the specific metabolic adaptations of torpor, as it is used by many species from temperate zones. This notably includes the endocrine changes involved in fat- and food-storing hibernating species, explaining biomedical implications of MR depression. We further compare adaptive mechanisms occurring in opportunistic vs. seasonal heterotherms, such as tropical and sub-tropical species. Such comparisons bring new insights into the metabolic origins of hibernation among tropical species, including resistance mechanisms to oxidative stress. The second section of this review emphasizes the mechanisms enabling heterotherms to protect their key organs against potential threats, such as reactive oxygen species, associated with the torpid state. We notably address the mechanisms of cellular rehabilitation and protection during torpor and hibernation, with an emphasis on the brain, a central organ requiring protection during torpor and recovery. Also, a special focus is given to the role of an ubiquitous and readily-diffusing molecule, hydrogen sulfide (H2S), in protecting against ischemia-reperfusion damage in various organs over the torpor-arousal cycle and during the torpid state. We conclude that (i) the flexibility of torpor use as an adaptive strategy enables different heterothermic species to substantially suppress their energy needs during periods of severely reduced food availability, (ii) the torpor phenotype implies marked metabolic adaptations from the whole organism down to cellular and molecular levels, and (iii) the torpid state is associated with highly efficient rehabilitation and protective mechanisms ensuring the continuity of proper bodily functions. Comparison of mechanisms in monotremes and marsupials is warranted for understanding the origin and evolution of mammalian torpor.

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Section: Protective Mechanisms During the State Of Metabolic Depressimentioning

confidence: 99%

The Torpid State: Recent Advances in Metabolic Adaptations and Protective Mechanisms†

et al. 2021

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“…Other cardiac adaptions during hibernation, such as decreased functional measures of myocardial velocities 39 may also be operative. Finally, a metabolic switch that shunts choline to generate betaine instead of the pro-atherogenic toxin Trimetylamine N-oxide (TMAO) during hibernation could hold clues for novel treatment options in burden of lifestyle diseases 40 .…”

Section: Discussionmentioning

confidence: 99%

Potential natural immunization against atherosclerosis in hibernating bears

Samal

Fröbert

Kindberg

et al. 2021

Sci Rep

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Brown bears (Ursus arctos) hibernate for 5–6 months during winter, but despite kidney insufficiency, dyslipidemia and inactivity they do not seem to develop atherosclerosis or cardiovascular disease (CVD). IgM antibodies against phosphorylcholine (anti-PC) and malondialdehyde (anti-MDA) are associated with less atherosclerosis, CVD and mortality in uremia in humans and have anti-inflammatory and other potentially protective properties. PC but not MDA is exposed on different types of microorganisms. We determine anti-PC and anti-MDA in brown bears in summer and winter. Paired serum samples from 12 free ranging Swedish brown bears were collected during hibernation in winter and during active state in summer and analyzed for IgM, IgG, IgG1/2 and IgA anti-PC and anti-MDA by enzyme linked immunosorbent assay (ELISA). When determined as arbitrary units (median set at 100 for summer samples), significantly raised levels were observed in winter for anti-PC subclasses and isotypes, and for IgA anti-PC the difference was striking; 100 IQR (85.9–107.9) vs 782.3, IQR (422.8–1586.0; p < 0.001). In contrast, subclasses and isotypes of anti-MDA were significantly lower in winter except IgA anti-MDA, which was not detectable. Anti-PCs are significantly raised during hibernation in brown bears; especially IgA anti-PC was strikingly high. In contrast, anti-MDA titers was decreased during hibernation. Our observation may represent natural immunization with microorganisms during a vulnerable period and could have therapeutic implications for prevention of atherosclerosis.

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“…In particular betaine levels, a primary source of methyl donors, is derived via the same biochemical pathway as TMAO, albeit on a different branch. It is therefore of note, that we recently reported that free-ranging brown bears may turn on a metabolic switch that in hibernation shunts choline to generate betaine instead of TMAO [61], thus decreasing inflammatory burden and enabling epigenetic changes in preparation for the metabolic changes occurring on emergence from hibernation. Characterisation and better understanding of such an adaptive switch turning on and off TMAO generation could hold clues for novel treatment options in burden of lifestyle diseases.…”

Section: Figure 1 Dietary Intake Tmao Metabolism and Disease Riskmentioning

confidence: 94%

A biomimetic natural sciences approach to understanding the mechanisms of ageing in burden of lifestyle diseases

et al. 2021

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The worldwide landscape of an ageing population and age-related disease brings with it huge socio-economic and public healthcare concerns across nations. Correspondingly, monumental human and financial resources have been invested in biomedical research, with a mission to decode the mechanisms of ageing and how these contribute to age-related disease. Multiple hallmarks of ageing have been identified that are common across taxa, highlighting their fundamental importance. These include dysregulated mitochondrial metabolism and telomeres biology, epigenetic modifications, cell–matrix interactions, proteostasis, dysregulated nutrient sensing, stem cell exhaustion, inflammageing and immuno-senescence. While our understanding of the molecular basis of ageing is improving, it remains a complex and multifactorial process that remains to be fully understood. A key aspect of the shortfall in our understanding of the ageing process lies in translating data from standard animal models to humans. Consequently, we suggest that a ‘biomimetic’ and comparative approach, integrating knowledge from species in the wild, as opposed to inbred genetically homogenous laboratory animals, can provide powerful insights into human ageing processes. Here we discuss some particularities and comparative patterns among several species from the animal kingdom, endowed with longevity or short lifespans and unique metabolic profiles that could be potentially exploited to the understanding of ageing and age-related diseases. Based upon lessons from nature, we also highlight several avenues for renewed focus in the pathophysiology of ageing and age-related disease (i.e. diet-microbiome-health axis, oxidative protein damage, adaptive homoeostasis and planetary health). We propose that a biomimetic alliance with collaborative research from different disciplines can improve our understanding of ageing and age-related diseases with long-term sustainable utility.

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Insights in the regulation of trimetylamine N-oxide production using a comparative biomimetic approach suggest a metabolic switch in hibernating bears

Cited by 23 publications

References 101 publications

The Torpid State: Recent Advances in Metabolic Adaptations and Protective Mechanisms†

The Torpid State: Recent Advances in Metabolic Adaptations and Protective Mechanisms†

Potential natural immunization against atherosclerosis in hibernating bears

A biomimetic natural sciences approach to understanding the mechanisms of ageing in burden of lifestyle diseases

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