Is metabolic rate a universal ‘pacemaker’ for biological processes?

A common, long‐held belief is that metabolic rate drives the rates of various biological, ecological and evolutionary processes. Although this metabolic pacemaker view (as assumed by the recent, influential ‘metabolic theory of ecology’) may be true in at least some situations (e.g. those involving moderate temperature effects or physiological processes closely linked to metabolism, such as heartbeat and breathing rate), it suffers from several major limitations, including: (i) it is supported chiefly by indirect, correlational evidence (e.g. similarities between the body‐size and temperature scaling of metabolic rate and that of other biological processes, which are not always observed) – direct, mechanistic or experimental support is scarce and much needed; (ii) it is contradicted by abundant evidence showing that various intrinsic and extrinsic factors (e.g. hormonal action and temperature changes) can dissociate the rates of metabolism, growth, development and other biological processes; (iii) there are many examples where metabolic rate appears to respond to, rather than drive the rates of various other biological processes (e.g. ontogenetic growth, food intake and locomotor activity); (iv) there are additional examples where metabolic rate appears to be unrelated to the rate of a biological process (e.g. ageing, circadian rhythms, and molecular evolution); and (v) the theoretical foundation for the metabolic pacemaker view focuses only on the energetic control of biological processes, while ignoring the importance of informational control, as mediated by various genetic, cellular, and neuroendocrine regulatory systems. I argue that a comprehensive understanding of the pace of life must include how biological activities depend on both energy and information and their environmentally sensitive interaction. This conclusion is supported by extensive evidence showing that hormones and other regulatory factors and signalling systems coordinate the processes of growth, metabolism and food intake in adaptive ways that are responsive to an organism's internal and external conditions. Metabolic rate does not merely dictate growth rate, but is coadjusted with it. Energy and information use are intimately intertwined in living systems: biological signalling pathways both control and respond to the energetic state of an organism. This review also reveals that we have much to learn about the temporal structure of the pace of life. Are its component processes highly integrated and synchronized, or are they loosely connected and often discordant? And what causes the level of coordination that we see? These questions are of great theoretical and practical importance.     

Somewhat in control — the role of transcription in regulating microbial metabolic fluxes

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FiatFlux – a software for metabolic flux analysis from <Superscript>13</Superscript>C-glucose experiments

Background  

Quantitative knowledge of intracellular fluxes is important for a comprehensive characterization of metabolic networks and their functional operation. In contrast to direct assessment of metabolite concentrations, in vivo metabolite fluxes must be inferred indirectly from measurable quantities in ¹³C experiments. The required experience, the complicated network models, large and heterogeneous data sets, and the time-consuming set-up of highly controlled experimental conditions largely restricted metabolic flux analysis to few expert groups. A conceptual simplification of flux analysis is the analytical determination of metabolic flux ratios exclusively from MS data, which can then be used in a second step to estimate absolute in vivo fluxes.     

Prebiotic metabolic networks?

A prebiotic origin of metabolism has been proposed as one of several scenarios for the origin of life. In their recent work, Ralser and colleagues (Keller et al, 2014 ) observe an enzyme‐free, metabolism‐like reaction network under conditions reproducing a possible prebiotic environment.     

NaCl induced metabolic changes in the diazotrophic cyanobacterium <Emphasis Type="Italic">Anabaena cylindrica</Emphasis>

NaCl induced changes in fatty acid composition and nitrogenase, glutamine synthetase (GS) and nitrate reductase (NR) activities have been studied in a diazotrophic cyanobacterium Anabaena cylindrica. GC-MS analysis revealed that the cellular fatty acid composition of NaCl untreated cells of A. cylindrica contained saturated and unsaturated fatty acids in high (85.15%) and low (13.17%) proportions, respectively. In contrast, NaCl adapted cells of A. cylindrica had reduced and increased levels of saturated (45.2%) and unsaturated (40%) fatty acids, respectively. It had a higher overall level of fatty acid unsaturation under NaCl stress mainly due to increase in C12:4, C10:1, C16:1 and C18:2 constituents. The activities of nitrogenase, GS and NR were reduced significantly in NaCl adapted cells as compared to its NaCl untreated counterparts.     

Cold stress and acclimation – what is important for metabolic adjustment?

As sessile organisms, plants are unable to escape from the many abiotic and biotic factors that cause a departure from optimal conditions of growth and development. Low temperature represents one of the most harmful abiotic stresses affecting temperate plants. These species have adapted to seasonal variations in temperature by adjusting their metabolism during autumn, increasing their content of a range of cryo‐protective compounds to maximise their cold tolerance. Some of these molecules are synthesised de novo. The down‐regulation of some gene products represents an additional important regulatory mechanism. Ways in which plants cope with cold stress are described, and the current state of the art with respect to both the model plant Arabidopsis thaliana and crop plants in the area of gene expression and metabolic pathways during low‐temperature stress are discussed.     

Influences of −482C&gt;T and 3238G&gt;C polymorphisms of the <Emphasis Type="Italic">Apolipoprotein C3</Emphasis> gene on prevalence of metabolic syndrome

Apolipoprotein C3 (ApoC3) plays a regulatory role in triglyceride (TG) metabolism. The higher level of TG can be a cause in pathogenesis of the vascular diseases or metabolic syndrome (MetS). In this study, we examined the associations of ApoC3 polymorphisms (?482C>T rs2854117 and 3238G>C rs5128) with Korean MetS patients. A total of 835 subjects were investigated, including 320 patients with MetS and 515 healthy subjects. The genotype analysis of the ApoC3 polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism methods. Of the two polymorphisms studied, we observed a significant difference in the ?482C>T polymorphism between the MetS and control groups. The TT genotype of the ?482C>T polymorphism was associated with increased risk for MetS, compared with the controls (OR 1.627, 95 % CI 1.075–2.463, P = 0.021). The association was female-specific. No associations were found for the risk of MetS in the 3238G>C polymorphism. Haplotypes composed of two polymorphisms, however, were associated with MetS susceptibility in only male group. The 3238G>C polymorphism was significantly associated with TG levels (P = 0.013). Our data suggest that the ApoC3 ?482C>T polymorphism is associated with increased MetS susceptibility in the Korean population.     

Higher resting metabolic rate in long-lived breeding Ansell’s mole-rats (<Emphasis Type="Italic">Fukomys anselli</Emphasis>)

Background

Reproduction is an energetically expensive process that supposedly impairs somatic integrity in the long term, because resources are limited and have to be allocated between reproduction and somatic maintenance, as predicted by the life history trade-off model. The consequence of reduced investment in somatic maintenance is a gradual deterioration of function, i.e. senescence. However, this classical trade-off model gets challenged by an increasing number of contradicting studies. Here we report about an animal model, which adds more complexity to the ongoing debate. Ansell’s mole-rats are long-lived social subterranean rodents with only the founder pair reproducing, while most of their offspring remain in the parental burrow system and do not breed. Despite of a clear reproductive trade-off, breeders live up to twice as long as non-breeders, a unique feature amongst mammals.

Methods

We investigated mass-specific resting metabolic rates (msRMR) of breeders and non-breeders to gain information about the physiological basis underlying the reproduction-associated longevity in Ansell’s mole-rats. We assessed the thermoneutral zone (TNZ) for breeders and non-breeders separately by means of indirect calorimetry. We applied generalized linear mixed-effects models for repeated measurements using the msRMR in the respective TNZs.

Results

TNZ differed between reproductive and non-reproductive Ansell’s mole-rats. Contrary to classical aging models, the shorter-lived non-breeders had significantly lower msRMR within the thermoneutral zone compared to breeders.

Conclusion

This is the first study reporting a positive correlation between msRMR and lifespan based on reproductive status. Our finding contradicts common aging theories, but supports recently introduced models which do not necessarily link reproductive trade-offs to lifespan reduction.

     

Metabolic theory or metabolic models?

The metabolic theory of ecology (MTE) claims to derive ecological relationships from the structure of resource distribution networks, which is assumed to determine the scaling of metabolism with body mass, and from the effect of temperature on the rate of biological processes. MTE is controversial. I propose that some of the controversy stems from the implicit adoption of different views of science by the proponents and critics of MTE. The perspective of proponents is consistent with the theory-centric view of science called the received view, whereas many of the critics implicitly adopt an alternative view consistent with a model-centric view of science. I propose that adopting the model-centric view can help to settle some of the differences among proponents and critics of MTE.     

Can variation in standard metabolic rate explain context‐dependent performance of farmed Atlantic salmon offspring?

Escaped farmed Atlantic salmon interbreed with wild Atlantic salmon, leaving offspring that often have lower success in nature than pure wild salmon. On top of this, presence of farmed salmon descendants can impair production of wild‐type recruits. We hypothesize that both these effects connect with farmed salmon having acquired higher standard metabolic rates (SMR, the energetic cost of self‐maintenance) during domestication. Fitness‐related advantages of phenotypic traits associated with both high SMR and farmed salmon (e.g., social dominance) depend on environmental conditions, such as food availability. We hypothesize that farmed offspring have an advantage at high food availability due to, for example, dominance behavior but suffer increased risks of starvation when food is scarce because this behavior is energy‐demanding. To test these hypotheses, we first compare embryo SMR of pure farmed, farmed‐wild hybrids and pure wild offspring. Next, we test early‐life performance (in terms of survival and growth) of hybrids relative to that of their wild half‐siblings, as well as their competitive abilities, in semi‐natural conditions of high and low food availability. Finally, we test how SMR affects early‐life performance at high and low food availability. We find inconclusive support for the hypothesis that domestication has induced increased SMR. Further, wild and hybrid juveniles had similar survival and growth in the semi‐natural streams. Yet, the presence of hybrids led to decreased survival of their wild half‐siblings. Contrary to our hypothesis about context‐dependency, these effects were not modified by food availability. However, wild juveniles with high SMR had decreased survival when food was scarce, but there was no such effect at high food availability. This study provides further proof that farmed salmon introgression may compromise the viability of wild salmon populations. We cannot, however, conclude that this is connected to alterations in the metabolic phenotype of farmed salmon.     

Two approaches for metabolic pathway analysis?

Metabolic pathway analysis is becoming increasingly important for assessing inherent network properties in (reconstructed) biochemical reaction networks. Of the two most promising concepts for pathway analysis, one relies on elementary flux modes and the other on extreme pathways. These concepts are closely related because extreme pathways are a subset of elementary modes. Here, the common features, differences and applicability of these concepts are discussed. Assessing metabolic systems by the set of extreme pathways can, in general, give misleading results owing to the exclusion of possibly important routes. However, in certain network topologies, the sets of elementary modes and extreme pathways coincide. This is quite often the case in realistic applications. In our opinion, the unification of both approaches into one common framework for metabolic pathway analysis is necessary and achievable.     

Enhanced uridine 5′-monophosphate production by whole cell of <Emphasis Type="Italic">Saccharomyces cerevisiae</Emphasis> through rational redistribution of metabolic flux

A whole-cell biocatalytic process for uridine 5′-monophosphate (UMP) production from orotic acid by Saccharomyces cerevisiae was developed. To rationally redistribute the metabolic flux between glycolysis and pentose phosphate pathway, statistical methods were employed first to find out the critical factors in the process. NaH₂PO₄, MgCl₂ and pH were found to be the important factors affecting UMP production significantly. The levels of these three factors required for the maximum production of UMP were determined: NaH₂PO₄ 22.1 g/L; MgCl₂ 2.55 g/L; pH 8.15. An enhancement of UMP production from 6.12 to 8.13 g/L was achieved. A significant redistribution of metabolic fluxes was observed and the underlying mechanism was discussed.     

Prematurity--another example of perinatal metabolic programming?

Low birth weight is associated with both later adult diseases such as type 2 diabetes mellitus and a number of metabolic abnormalities, the foremost of which is insulin resistance. Indeed the link between an adverse perinatal environment, manifested by low birth weight, and adult life pathology may be an early, permanent reduction in insulin sensitivity. A reduction in insulin sensitivity has been demonstrated in small for gestational age (SGA), term subjects from childhood through to adulthood. Less is known about children born premature into an adverse neonatal environment. We present data demonstrating that premature infants also have metabolic abnormalities similar to those observed in term, SGA children and that these occur irrespective of whether they are SGA or appropriate for gestational age (AGA).     

How will bioinformatics influence metabolic engineering?

Ten microbial genomes have been fully sequenced to date, and the sequencing of many more genomes is expected to be completed before the end of the century. The assignment of function to open reading frames (ORFs) is progressing, and for some genomes over 70% of functional assignments have been made. The majority of the assigned ORFs relate to metabolic functions. Thus, the complete genetic and biochemical functions of a number of microbial cells may be soon available. From a metabolic engineering standpoint, these developments open a new realm of possibilities. Metabolic analysis and engineering strategies can now be built on a sound genomic basis. An important question that now arises; how should these tasks be approached? Flux-balance analysis (FBA) has the potential to play an important role. It is based on the fundamental principle of mass conservation. It requires only the stoichiometric matrix, the metabolic demands, and some strain specific parameters. Importantly, no enzymatic kinetic data is required. In this article, we show how the genomically defined microbial metabolic genotypes can be analyzed by FBA. Fundamental concepts of metabolic genotype, metabolic phenotype, metabolic redundancy and robustness are defined and examples of their use given. We discuss the advantage of this approach, and how FBA is expected to find uses in the near future. FBA is likely to become an important analysis tool for genomically based approaches to metabolic engineering, strain design, and development.     

Does skeletal muscle have an ‘epi’‐memory? The role of epigenetics in nutritional programming,metabolic disease,aging and exercise

Skeletal muscle mass, quality and adaptability are fundamental in promoting muscle performance, maintaining metabolic function and supporting longevity and healthspan. Skeletal muscle is programmable and can ‘remember’ early‐life metabolic stimuli affecting its function in adult life. In this review, the authors pose the question as to whether skeletal muscle has an ‘epi’‐memory? Following an initial encounter with an environmental stimulus, we discuss the underlying molecular and epigenetic mechanisms enabling skeletal muscle to adapt, should it re‐encounter the stimulus in later life. We also define skeletal muscle memory and outline the scientific literature contributing to this field. Furthermore, we review the evidence for early‐life nutrient stress and low birth weight in animals and human cohort studies, respectively, and discuss the underlying molecular mechanisms culminating in skeletal muscle dysfunction, metabolic disease and loss of skeletal muscle mass across the lifespan. We also summarize and discuss studies that isolate muscle stem cells from different environmental niches in vivo (physically active, diabetic, cachectic, aged) and how they reportedly remember this environment once isolated in vitro. Finally, we will outline the molecular and epigenetic mechanisms underlying skeletal muscle memory and review the epigenetic regulation of exercise‐induced skeletal muscle adaptation, highlighting exercise interventions as suitable models to investigate skeletal muscle memory in humans. We believe that understanding the ‘epi’‐memory of skeletal muscle will enable the next generation of targeted therapies to promote muscle growth and reduce muscle loss to enable healthy aging.     

Association of <Emphasis Type="Italic">IL-10</Emphasis> gene (−1082A&gt;G, −819C&gt;T and −592C&gt;A) polymorphism and its serum level with metabolic syndrome of north Indian subjects

Metabolic syndrome (MetS) is an inflammatory disorder, in which various cytokines play important role in tilting balance towards disease state. Interleukin-10 (IL-10) is an important antiinflammatory cytokine, but its genetic polymorphisms and serum levels in Indian MetS subjects are unknown. Three IL-10 gene polymorphisms (?1082A >G (rs1800896), ?819C >T (rs1800872) and ?592C >A (rs1800871)) were genotyped with PCR-RFLP in MetS subjects (n = 384) and age/sex matched control subjects (n = 386). Serum IL-10 was measured using enzyme-linked immunosorbent assay. Serum IL-10 level was significantly low in MetS subject and significantly correlated with clinicobiochemical parameters of MetS. Of three investigated promoter polymorphisms, IL-10 –819C > T and –592C >A were significantly associated with risk of MetS. The mutant alleles ?819T and ?592A of IL-10 gene polymorphism were significantly higher in MetS subjects compared to controls. Of the four different haplotypes obtained, common ACC haplotype and rare GTA haplotype of IL-10 polymorphisms were associated with MetS. The mean of fasting insulin and HOMA-IR were significantly different between the genotypes of both ?819 C >T and ?592C >A polymorphisms of IL-10 in MetS subjects. These results suggested that polymorphisms in IL-10 gene (?819C >T and ?592C >A), haplotypes (ACC and GTA) and serum level are significantly associated with risk of MetS. IL-10 ?819C >T and ?592C >A polymorphic variants are also significantly associated with insulin level and homeostasis model assessment-insulin resistance in north Indian MetS subjects.     

Synbiotic effects of β-glucans from cauliflower mushroom and <Emphasis Type="Italic">Lactobacillus fermentum</Emphasis> on metabolic changes and gut microbiome in estrogen-deficient rats

Background

We investigated whether the long-term consumption of a symbiotic formulation with Lactobacillus fermentum (probiotic) and β-glucan from cauliflower mushroom (prebiotic) would delay the progression of post-menopausal symptoms in ovariectomized (OVX) rats and explored their mechanisms of action, including changes in gut microbiota.

Methods

OVX rats were fed with high-fat diets containing 1% dextrin (control), 1% lyophilized cauliflower mushroom extract (CFM), 0.1% L. fermentum JS (LFE), 1% CFM plus 0.1% LFE (CFLF), or 30 μg 17β-estradiol/kg body weight (positive-control) for 8 weeks.

Results

CFM contained 95.8% β-glucans. OVX increased the ratio of Firmicutes and Bacteroidetes in the large intestines. Only CFLF lowered tail skin temperature without increasing serum 17β-estradiol and uterine index. Visceral fat mass was lower in CFLF and positive-control groups by increasing daily energy expenditure and fat oxidation. Dyslipidemia induced by OVX was improved by CFM and CFLF as much as in the positive-control group. Homeostasis model assessment estimate of insulin resistance was lower in CFLF than in the positive-control. Hepatic insulin signaling (pAkt?GSK-3β) was potentiated in the ascending order of the control, LFE, CFM, CFLF, and positive-control. AMPK phosphorylation showed similar patterns of hepatic insulin signaling but LFE increased it more than CFM. The changes in gut microbiota were prevented by CFLF in OVX rats, and the ratio of Firmicutes and Bacteroidetes in the CFLF was similar to the positive-control group.

Conclusion

OVX changed gut microbiota and was associated with menopausal symptoms; however, the synbiotics, CFM and LFE, prevented menopausal symptoms and improved the gut microbiota in estrogen-deficient rats.

     

Do immunological,endocrine and metabolic traits fall on a single Pace‐of‐Life axis? Covariation and constraints among physiological systems

Variation in demographic and physiological attributes of life history is thought to fall on one single axis, a phenomenon termed the Pace-of-Life. A slow Pace-of-Life is characterized by low annual reproduction, long life span and low metabolic rate, a fast Pace-of-Life by the opposite characteristics. The existence of a single axis has been attributed to constraints among physiological mechanisms that are thought to restrict evolutionary potential. In that case, physiological traits should covary in the same fashion at the levels of individual organisms and species. We examined covariation at the levels of individual and subspecies in three physiological systems (metabolic, endocrine and immune) using four stonechat subspecies with distinct life-history strategies in a common-garden set-up. We measured basal metabolic rate, corticosterone as endocrine measure and six measures of constitutive immunity. Metabolic rate covaried with two indices of immunity at the individual level, and with corticosterone concentrations and one index of immunity at the subspecies level, but not with other measures. The different patterns of covariation among individuals and among subspecies demonstrate that links among physiological traits are loose and suggest that these traits can evolve independent of each other.