AMP-activated protein kinase: an emerging drug target to regulate imbalances in lipid and carbohydrate metabolism to treat cardio-metabolic diseases: Thematic Review Series: New Lipid and Lipoprotein Targets for the Treatment of Cardiometabolic Diseases

The adenosine monophosphate-activated protein kinase (AMPK) is a metabolic sensor of energy metabolism at the cellular as well as whole-body level. It is activated by low energy status that triggers a switch from ATP-consuming anabolic pathways to ATP-producing catabolic pathways. AMPK is involved in a wide range of biological activities that normalizes lipid, glucose, and energy imbalances. These pathways are dysregulated in patients with metabolic syndrome (MetS), which represents a clustering of major cardiovascular risk factors including diabetes, lipid abnormalities, and energy imbalances. Clearly, there is an unmet medical need to find a molecule to treat alarming number of patients with MetS. AMPK, with multifaceted activities in various tissues, has emerged as an attractive drug target to manage lipid and glucose abnormalities and maintain energy homeostasis. A number of AMPK activators have been tested in preclinical models, but many of them have yet to reach to the clinic. This review focuses on the structure-function and role of AMPK in lipid, carbohydrate, and energy metabolism. The mode of action of AMPK activators, mechanism of anti-inflammatory activities, and preclinical and clinical findings as well as future prospects of AMPK as a drug target in treating cardio-metabolic disease are discussed.     

Bacterial redox sensors

Redox reactions pervade living cells. They are central to both anabolic and catabolic metabolism. The ability to maintain redox balance is therefore vital to all organisms. Various regulatory sensors continually monitor the redox state of the internal and external environments and control the processes that work to maintain redox homeostasis. In response to redox imbalance, new metabolic pathways are initiated, the repair or bypassing of damaged cellular components is coordinated and systems that protect the cell from further damage are induced. Advances in biochemical analyses are revealing a range of elegant solutions that have evolved to allow bacteria to sense different redox signals.     

Autumn-winter energetics of Holarctic tree squirrels:a review

Similarities in general size, geometry, lifestyle, and environment mean that certain energetic constraints are common and peculiar to Holarctic tree squirrels as a group. Holarctic tree squirrels are relatively small, diurnal mammals which, in association with their food niche, maintain activity throughout the autumn-winter period. Despite this, they exhibit no major morphological or physiological adaptations to minimize energy expenditure at low temperatures; on the contrary, both basal metabolism and conductance are higher than expected on the grounds of physical size. When they are active energy expenditure is therefore strongly influenced by effective ambient temperature for these species when active in their natural autumn-winter environments. Nest use allows near-basal metabolism at most natural ambient temperatures. The balance of economical inactivity against feeding rewards offset by cold exposure must therefore be a crucial aspect of the lifestyle of these squirrels.     

AMPK: a nutrient and energy sensor that maintains energy homeostasis

AMP-activated protein kinase (AMPK) is a crucial cellular energy sensor. Once activated by falling energy status, it promotes ATP production by increasing the activity or expression of proteins involved in catabolism while conserving ATP by switching off biosynthetic pathways. AMPK also regulates metabolic energy balance at the whole-body level. For example, it mediates the effects of agents acting on the hypothalamus that promote feeding and entrains circadian rhythms of metabolism and feeding behaviour. Finally, recent studies reveal that AMPK conserves ATP levels through the regulation of processes other than metabolism, such as the cell cycle and neuronal membrane excitability.     

THE INFLUENCE OF BROOD SIZE ON THE ENERGY METABOLISM AND WATER LOSS OF NESTLING GREAT TITS PARUS MAJOR MAJOR

At normal outdoor temperatures there is a distinct influence of brood size on the heat production of ten-day-old Great Tits. One ten-day-old nestling proved unable to maintain its body temperature at 12^°C. Two ten-day-old tits together in one nestbox at 12^Á°C were able to elevate the air temperature sufficiently to maintain homoiothermia. The same of course holds for tits in larger broods.
At an air temperature of 18^°C, six or seven ten-day-old tits placed in a nestbox elevated the air temperature to a level at which they almost reached a state of hyperthermia: their metabolism was at the basal level. The basal metabolism of a ten-day-old tit was found to be slightly more than 0–1800 kcal/h. The metabolism intensity of 12 tits in a nestbox at 12^°C was of the same order of magnitude.
Tits in broods comprising more than 12 or 13 nestlings at normal outdoor temperatures probably develop hyperthermia, which is unfavourable both for their energy and for their water balance.     

The Opposing Actions of Target of Rapamycin and AMP-Activated Protein Kinase in Cell Growth Control

Cell growth is a highly regulated, plastic process. Its control involves balancing positive regulation of anabolic processes with negative regulation of catabolic processes. Although target of rapamycin (TOR) is a major promoter of growth in response to nutrients and growth factors, AMP-activated protein kinase (AMPK) suppresses anabolic processes in response to energy stress. Both TOR and AMPK are conserved throughout eukaryotic evolution. Here, we review the fundamentally important roles of these two kinases in the regulation of cell growth with particular emphasis on their mutually antagonistic signaling.An efficient homeostatic response to maintain cellular energy despite a noncontinuous supply of nutrients is crucial for the survival of organisms. Cells have, therefore, evolved a host of molecular pathways to sense both intra- and extracellular nutrients and thereby quickly adapt their metabolism to changing conditions. The target of rapamycin (TOR) and AMP-activated protein kinase (AMPK) signaling pathways control growth and metabolism in a complementary manner with TOR promoting anabolic processes under nutrient- and energy-rich conditions, whereas AMPK promotes a catabolic response when cells are low on nutrients and energy. Both pathways are highly conserved from yeast to human. This review summarizes the cross talk between TOR and AMPK in different organisms.     

瘦素水平与代谢综合症的关系

随着代谢综合症在世界范围内的广为流行,已经引起人们的高度重视.代谢综合征以肥胖和代谢异常为特征,胰岛素抵抗为主要的病理机制.瘦素主要来源于脂肪组织,是调节体内脂肪储量和维持能量平衡的一种内分泌激素.瘦素缺乏和瘦素抵抗不仅可以直接引起胰岛素抵抗,而且可以通过导致肥胖继而参与胰岛素抵抗的发生,最终引起代谢综合征.瘦素作为一种新的代谢综合征致病因子,参与代谢综合征的发生发展,故调节瘦素水平为临床治疗代谢综合症提供了新的思路和方法.本文综述了瘦素水平与代谢综合症的关系,以及调节瘦素水平治疗代谢综合征的方法.     

AMPK: a link between metabolism and reproduction?

5'AMP-activated protein kinase (AMPK) is a serine/threonine kinase that acts as a fuel gauge in regulating energy metabolism. It restores cellular ATP levels by switching on catabolic pathways and switching off anabolic pathways. Some evidence indicates that AMPK could be also implicated in reproductive functions such as granulosa cell steroidogenesis and nuclear oocyte maturation in several species. Some metabolic hormones such as leptin, resistin, adiponectin (three adipokines) and ghrelin may in part act through the AMPK signaling. These hormones are also involved in the control of the reproductive functions at the hypothalamus-pituitary-gonadal axis level in both male and female. Thus, AMPK could be one of the signaling pathways controlling the interactions between energy balance and reproduction. The reproductive system is tightly coupled with energy balance, and thereby metabolic abnormalities can lead to the development of some physiopathological situations such as the polycystic ovary syndrome (PCOS). Women with PCOS show altered fertility mostly associated with metabolic disorders such as insulin-resistance, hyperinsulinemia and/or dyslipidemia. Metformin, an insulin-sensitizer, is used for the treatment of women with PCOS. It restores subnormal fertility and energy balance. Recent studies show that AMPK is involved in the mechanism of action of metformin. Thus, it may be a therapeutic target. However, further investigations are necessary to elucidate the functions of AMPK in both metabolic and reproductive tissues.     

雌激素影响物质和能量代谢的中枢机制

雌激素与糖尿病的发生和发展有密切关系。新近研究表明,雌激素受体(estrogen receptor,ER)对物质代谢和能量平衡具有重要调节作用。雌激素可由核内ER介导,通过基因组机制,或膜上ER通过磷脂酰肌醇3-激酶/蛋白激酶B及胞外信号调节激酶信号转导通路,调节下丘脑神经元摄食和厌食神经肽的表达。下丘脑ERα基因沉默小鼠表现出典型的代谢综合征症状,提示中枢ERα能够影响外周能量代谢。进一步研究发现,中枢ERα和胰岛素以及瘦素信号转导通路存在交互作用。因此,阐明中枢ER调控能量代谢的机制,可为临床防治雌激素紊乱导致的糖和能量代谢异常提供新的思路。     

Hummingbird foraging and the relation between bioenergetics and behaviour

Because of their small size and expensive mode of flight, hummingbirds display some of the highest known mass-specific rates of aerobic metabolism among vertebrates. High enzymatic flux capacities through pathways of carbohydrate and long-chain fatty acid oxidation indicate that either substrate can fuel flight. Although hummingbirds are known to rely on fat to fuel migratory flight, short foraging bouts are fueled by the oxidation of carbohydrate, not fat. This allows birds refueling at meadows during migration to deposit fat at higher rates and avoids the energetic inefficiency that results from synthesizing fat from dietary sugar, and then breaking down the fat to fuel foraging flight. On cold mornings in subalpine meadows, refueling hummingbirds achieve net energy gain despite the high energetic costs of thermoregulation and flight. In doing so, they sustain the highest known time-averaged metabolic rates among vertebrates. However, low sucrose concentrations, provided in volumes large enough to allow the maintenance of energy balance at low temperature, result in energy deficit and mass loss. The problem of disposing of dietary water at low ambient temperature when intake rates are elevated suggests that the kidneys may be involved in establishing the upper limit to intake rates and, therefore, maximum sustained metabolic rates. It is suggested that hummingbird behaviour and metabolism have coevolved to maximize net energy gain. Further, the energetics of hummingbird thermoregulation and flight may have influenced the evolution of sucrose content in floral nectar.     

The pathways of energy generation in filarial parasites

It has been commonly accepted that most adult filarial parasites use the glycolytic breakdown of carbohydrates to lactate as a preferred route to supply their energy requirements. Their ability to catabolize glucose by oxygen-dependent pathways is rather limited. An exception to this is the rodent filarial species Litomosoides carinii, which requires a unique type of aerobic glucose metabolism to maintain motor activity and survival. However, the prominent role of carbohydrates as energy substrates for filariids may no longer be tenable. Recent studies have shown that glutamine is a major energy source in filarial worms and that a fully oxidative mitochondrial metabolism can be employed for the utilization of this substrate.     

On the temperature-dependency of optimal nectar concentrations for birds.

In addition to the crucial need for energy balance, the metabolically-intense hummingbirds must maintain osmotic homeostasis by regulating salt and fluid balance. Hypothetically, flowers which have coevolved with pollination by hummingbirds could provide both energy and water balance simultaneously if they produced nectars of appropriate concentrations which depend upon environmental temperature. To the extent that this has not completely adjusted, hummingbirds exposed to cold and hot extremes in temperature will have problems of water excess or deficiency, respectively.     

Flux balance analysis of photoautotrophic metabolism

Photosynthesis is the principal process responsible for fixation of inorganic carbon dioxide into organic molecules with sunlight as the energy source. Potentially, many chemicals could be inexpensively produced by photosynthetic organisms. Mathematical modeling of photoautotrophic metabolism is therefore important to evaluate maximum theoretical product yields and to deeply understand the interactions between biochemical energy, carbon fixation, and assimilation pathways. Flux balance analysis based on linear programming is applied to photoautotrophic metabolism. The stoichiometric network of a model photosynthetic prokaryote, Synechocystis sp. PCC 6803, has been reconstructed from genomic data and biochemical literature and coupled with a model of the photophosphorylation processes. Flux map topologies for the hetero-, auto-, and mixotrophic modes of metabolism under conditions of optimal growth were determined and compared. The roles of important metabolic reactions such as the glyoxylate shunt and the transhydrogenase reaction were analyzed. We also theoretically evaluated the effect of gene deletions or additions on biomass yield and metabolic flux distributions.     

Multiple facets of anoxic metabolism and hydrogen production in the unicellular green alga Chlamydomonas reinhardtii

Many microbes in the soil environment experience micro-oxic or anoxic conditions for much of the late afternoon and night, which inhibit or prevent respiratory metabolism. To sustain the production of energy and maintain vital cellular processes during the night, organisms have developed numerous pathways for fermentative metabolism. This review discusses fermentation pathways identified for the soil-dwelling model alga Chlamydomonas reinhardtii, its ability to produce molecular hydrogen under anoxic conditions through the activity of hydrogenases, and the molecular flexibility associated with fermentative metabolism that has only recently been revealed through the analysis of specific mutant strains.     

AMPK: An odyssey of a metabolic regulator,a tumor suppressor,and now a contextual oncogene

Metabolic reprogramming is a unique but complex biochemical adaptation that allows solid tumors to tolerate various stresses that challenge cancer cells for survival. Under conditions of metabolic stress, mammalian cells employ adenosine monophosphate (AMP)-activated protein kinase (AMPK) to regulate energy homeostasis by controlling cellular metabolism. AMPK has been described as a cellular energy sensor that communicates with various metabolic pathways and networks to maintain energy balance. Earlier studies characterized AMPK as a tumor suppressor in the context of cancer. Later, a paradigm shift occurred in support of the oncogenic nature of AMPK, considering it a contextual oncogene. In support of this, various cellular and mouse models of tumorigenesis and clinicopathological studies demonstrated increased AMPK activity in various cancers. This review will describe AMPK's pro-tumorigenic activity in various malignancies and explain the rationale and context for using AMPK inhibitors in combination with anti-metabolite drugs to treat AMPK-driven cancers.     

Cofactor engineering for more efficient production of chemicals and biofuels

Cofactors are involved in numerous intracellular reactions and critically influence redox balance and cellular metabolism. Cofactor engineering can support and promote the biocatalysis process, even help driving thermodynamically unfavorable reactions forwards. To achieve efficient production of chemicals and biofuels, cofactor engineering strategies such as altering cofactor supply or modifying reactants' cofactor preference have been developed to maintain redox balance. This review focuses primarily on the effects of cofactor engineering on carbon and energy metabolism. Coupling carbon metabolism with cofactor engineering can promote large-scale production, and even offer possibilities for producing new products or converting new materials.     

Activity and energy expenditure

The influence of small changes in activity on energy expenditure and hence on energy requirements and energy balance is assessed. Evidence from direct and indirect calorimetry suggests that differences in spontaneous minor activity could readily alter 24-h energy expenditure by as much as 20%. This compares with values in the order of 10% for moderate overfeeding and somewhat less than this during mild cold exposure. Individual variability in 24-h energy expenditure can therefore be accounted for not only by differences in resting metabolism and the thermic responses to energy intake and temperature but also by differences in minor activity. Interactions between activity and environmental factors such as nutrition and temperature can modify the effect of activity on energy balance. Very little is known about mechanisms that could account for differences in spontaneous activity and these need to be the subject of future investigations.     

Redox-shuttling between chloroplast and cytosol: integration of intra-chloroplast and extra-chloroplast metabolism

Reducing equivalents produced in the chloroplast are essential for many key cellular metabolic enzyme reactions. Two redox shuttle systems transfer reductant out of the chloroplast; these systems consist of metabolite transporters, coupled with stromal and cytosolic dehydrogenase isozymes. The transporters function in the redox shuttle and also operate as key enzymes in carbon/nitrogen metabolism. To maintain adequate levels of reductant and proper metabolic balance, the shuttle systems are finely controlled. Also, in the leaves of C(4) plants, cell-specific division of carbon and nitrogen assimilation includes cell-specific localization of the redox shuttle systems. The redox shuttle systems are tightly linked to cellular metabolic pathways and are essential for maintaining metabolic balance between energy and reducing equivalents.     

Lipidomics in biomedical research-practical considerations

Lipids have many central physiological roles including as structural components of cell membranes, energy storage sources and intermediates in signaling pathways. Lipid-related disturbances are known to underlie many diseases and their co-morbidities. The emergence of lipidomics has empowered researchers to study lipid metabolism at the cellular as well as physiological levels at a greater depth than was previously possible. The key challenges ahead in the field of lipidomics in medical research lie in the development of experimental protocols and in silico techniques needed to study lipidomes at the systems level. Clinical questions where lipidomics may have an impact in healthcare settings also need to be identified, both from the health outcomes and health economics perspectives. This article is part of a Special Issue entitled: BBALIP_Lipidomics Opinion Articles edited by Sepp Kohlwein.