scholarly journals Sirtuin 1 and Sirtuin 3: Physiological Modulators of Metabolism

2012 ◽  
Vol 92 (3) ◽  
pp. 1479-1514 ◽  
Author(s):  
Ruben Nogueiras ◽  
Kirk M. Habegger ◽  
Nilika Chaudhary ◽  
Brian Finan ◽  
Alexander S. Banks ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Sirtuin 1 ◽  
Energy Status ◽  
Metabolic Processes ◽  
Sirtuin 3 ◽  
Nonalcoholic Fatty Liver ◽  
Cellular Energy ◽  
Diet Induced Obesity ◽  
Energy Stores

The sirtuins are a family of highly conserved NAD+-dependent deacetylases that act as cellular sensors to detect energy availability and modulate metabolic processes. Two sirtuins that are central to the control of metabolic processes are mammalian sirtuin 1 (SIRT1) and sirtuin 3 (SIRT3), which are localized to the nucleus and mitochondria, respectively. Both are activated by high NAD+ levels, a condition caused by low cellular energy status. By deacetylating a variety of proteins that induce catabolic processes while inhibiting anabolic processes, SIRT1 and SIRT3 coordinately increase cellular energy stores and ultimately maintain cellular energy homeostasis. Defects in the pathways controlled by SIRT1 and SIRT3 are known to result in various metabolic disorders. Consequently, activation of sirtuins by genetic or pharmacological means can elicit multiple metabolic benefits that protect mice from diet-induced obesity, type 2 diabetes, and nonalcoholic fatty liver disease.

Molecular Regulation of Energy Balance

2019 ◽  
Author(s):  
D. Grahame Hardie ◽  
A. Mark Evans
Keyword(s):  
Energy Balance ◽  
Energy Homeostasis ◽  
Adenine Nucleotides ◽  
Kinase Domain ◽  
Cellular Level ◽  
Whole Body ◽  
Energy Status ◽  
Α Subunit ◽  
Cellular Energy ◽  
Synthetic Drugs

AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that monitors the levels of AMP and ADP relative to ATP. If increases in AMP:ATP and/or ADP:ATP ratios are detected (indicating a reduction in cellular energy status), AMPK is activated by the canonical mechanism involving both allosteric activation and enhanced net phosphorylation at Thr172 on the catalytic subunit. Once activated, AMPK phosphorylates dozens of downstream targets, thus switching on catabolic pathways that generate ATP and switching off anabolic pathways and other energy-consuming processes. AMPK can also be activated by non-canonical mechanisms, triggered either by glucose starvation by a mechanism independent of changes in adenine nucleotides, or by increases in intracellular Ca2+ in response to hormones, mediated by the alternate upstream kinase CaMKK2. AMPK is expressed in almost all eukaryotic cells, including neurons, as heterotrimeric complexes comprising a catalytic α subunit and regulatory β and γ subunits. The α subunits contain the kinase domain and regulatory regions that interact with the other two subunits. The β subunits contain a domain that, with the small lobe of the kinase domain on the α subunit, forms the “ADaM” site that binds synthetic drugs that are potent allosteric activators of AMPK, while the γ subunits contain the binding sites for the classical regulatory nucleotides, AMP, ADP, and ATP. Although much undoubtedly remains to be discovered about the roles of AMPK in the nervous system, emerging evidence has confirmed the proposal that, in addition to its universal functions in regulating energy balance at the cellular level, AMPK also has cell- and circuit-specific roles at the whole-body level, particularly in energy homeostasis. These roles are mediated by phosphorylation of neural-specific targets such as ion channels, distinct from the targets by which AMPK regulates general, cell-autonomous energy balance. Examples of these cell- and circuit-specific functions discussed in this review include roles in the hypothalamus in balancing energy intake (feeding) and energy expenditure (thermogenesis), and its role in the brainstem, where it supports the hypoxic ventilatory response (breathing), increasing the supply of oxygen to the tissues during systemic hypoxia.

SnRK1 stimulates the histone H3K27me3 demethylase JMJ705 to regulate a transcriptional switch to control energy homeostasis

2021 ◽  
Author(s):  
Wentao Wang ◽  
Yue Lu ◽  
Junjie Li ◽  
Xinran Zhang ◽  
Fangfang Hu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Energy Homeostasis ◽  
Low Energy ◽  
Transcriptional Networks ◽  
Energy Status ◽  
Α Subunit ◽  
Cellular Energy ◽  
Energy Stress ◽  
Demethylase Activity ◽  
Regulated Gene Expression

Abstract Plant SNF1-Related Kinase1 (SnRK1) is an evolutionarily conserved energy-sensing protein kinase that orchestrates transcriptional networks to maintain cellular energy homeostasis when energy supplies become limited. However, the mechanism by which SnRK1 regulates this gene expression switch to gauge cellular energy status remains largely unclear. In this work, we show that the rice histone H3K27me3 demethylase JMJ705 is required for low energy stress tolerance in rice plants. The genetic inactivation of JMJ705 resulted in similar effects as those of the rice snrk1 mutant on the transcriptome, which impairs not only the promotion of the low energy stress-triggered transcriptional program but also the repression of the program under an energy-sufficient state. We show that the α-subunit of OsSnRK1 interacts with and phosphorylates JMJ705 to stimulate its H3K27me3 demethylase activity. Further analysis revealed that JMJ705 directly targets a set of low energy stress-responsive transcription factor genes. These results uncover the chromatin mechanism of SnRK1-regulated gene expression in both energy-sufficient and -limited states in plants and suggest that JMJ705 functions as an upstream regulator of the SnRK1α-controlled transcriptional network.

scholarly journals Can resveratrol help to maintain metabolic health?

2014 ◽  
Vol 73 (2) ◽  
pp. 271-277 ◽  
Author(s):  
Patrick Schrauwen ◽  
Silvie Timmers
Keyword(s):  
Type 2 Diabetes ◽  
Mitochondrial Function ◽  
Therapeutic Strategy ◽  
Metabolic Diseases ◽  
Human Subjects ◽  
Metabolic Health ◽  
Sirtuin 1 ◽  
Cellular Energy ◽  
Cellular Energy Metabolism

The number of people suffering from metabolic diseases is dramatically increasing worldwide. This stresses the need for new therapeutic strategies to combat this growing epidemic of metabolic diseases. A reduced mitochondrial function is one of the characteristics of metabolic diseases and therefore a target for intervention. Here we review the evidence that mitochondrial function may act as a target to treat and prevent type 2 diabetes mellitus, and, if so, whether these effects are due to reduction in skeletal muscle fat accumulation. We describe how exercise may affect these parameters and can be beneficial for type 2 diabetes. We next focus on alternative ways to improve mitochondrial function in a non-exercise manner. Thus, in 2003, resveratrol (3,5,4′-trihydroxystilbene) was discovered to be a small molecule activator of sirtuin 1, an important molecular target regulating cellular energy metabolism and mitochondrial homoeostasis. Rodent studies have clearly demonstrated the potential of resveratrol to improve various metabolic health parameters. Here we review data in human subjects that is available on the effects of resveratrol on metabolism and mitochondrial function and discuss how resveratrol may serve as a new therapeutic strategy to preserve metabolic health. We also discuss whether the effects of resveratrol are similar to the effects of exercise training and therefore if resveratrol can be considered as an exercise mimetic.

scholarly journals An Integrated View: Neuroadipocrinology of Diabesity

2014 ◽  
Vol 15 (2) ◽  
pp. 61-69 ◽  
Author(s):  
George N. Chaldakov ◽  
Marco Fiore ◽  
Gorana Ranćić ◽  
Jerzy Beltowski ◽  
Neşe Tunçel ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Energy Homeostasis ◽  
Interleukin 10 ◽  
Research Field ◽  
Sirtuin 1 ◽  
Paradigm Shifts ◽  
Cardiometabolic Diseases ◽  
The Status ◽  
Aquaporin 7

ABSTRACT Today’s achievements in systems biology and -omics sciences have facilitated a shift from studying individual molecules and tissues to characterising molecules and cells holistically. In this article, we attempt to discuss the status of a much-needed coherent view that integrates studies on neurobiology and adipobiology, as well as those on diabetes and obesity. Globally, cardiometabolic diseases (atherosclerosis, hypertension, type 2 diabetes mellitus, obesity, diabesity, and metabolic syndrome) are the most prevalent pathologies. In 2000, Astrup and Finer (Obes Rev 1: 57-59) wrote the following: “Since type 2 diabetes is obesity dependent, and obesity is the main aetiogical cause of type 2 diabetes, we propose the term ‘diabesity’ should be adopted.” Arguably, the research field of adipobiology has witnessed three major paradigm shifts since the discovery of leptin, an adipose-derived hormone, in 1994. Various neuroendocrine and neurotrophic factors are included in the growing list of endocrine and paracrine adipose-secreted signaling proteins collectively designated adipokines. These findings open a novel field of research known as neuroadipocrinology, a component of neuroendocrinology. Adipokines, including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), mediate multiple biological processes, such as food intake, immunity, inflammation, memory, mood, and metabolism. The effects on metabolism involve the maintenance of glucose, lipid and energy homeostasis as well as cardioprotection, neuroprotection, and aging. In this article, we highlight the role of metabotrophic factors (MTF) and the adipose- and nonadipose-derived biomolecules that mediate these effects. Recent results demonstrate that circulating and tissue levels of certain MTFs, e.g., adiponectin, NGF, BDNF, glucagon-like protein-1, sirtuin-1, interleukin- 10, and aquaporin-7, are altered in cardiometabolic diseases, including diabesity. Overall, this may cultivate a novel thinking for diabesity, herein also referred to as Homo diabesus.

scholarly journals Hypothalamic NAD+-Sirtuin Axis: Function and Regulation

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 396
Author(s):  
Eun Roh ◽  
Min-Seon Kim
Keyword(s):  
Energy Homeostasis ◽  
Therapeutic Potential ◽  
Energy Status ◽  
Transcriptional Responses ◽  
Cellular Energy ◽  
Global Health Care ◽  
Neuronal Functions ◽  
Care Problems ◽  
Circadian Physiology ◽  
Metabolic Regulators

The rapidly expanding elderly population and obesity endemic have become part of continuing global health care problems. The hypothalamus is a critical center for the homeostatic regulation of energy and glucose metabolism, circadian rhythm, and aging-related physiology. Nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase sirtuins are referred to as master metabolic regulators that link the cellular energy status to adaptive transcriptional responses. Mounting evidence now indicates that hypothalamic sirtuins are essential for adequate hypothalamic neuronal functions. Owing to the NAD+-dependence of sirtuin activity, adequate hypothalamic NAD+ contents are pivotal for maintaining energy homeostasis and circadian physiology. Here, we comprehensively review the regulatory roles of the hypothalamic neuronal NAD+-sirtuin axis in a normal physiological context and their changes in obesity and the aging process. We also discuss the therapeutic potential of NAD+ biology-targeting drugs in aging/obesity-related metabolic and circadian disorders.

scholarly journals A salt-induced kinase (SIK) is required for the metabolic regulation of sleep

2019 ◽  
Author(s):  
Jeremy J. Grubbs ◽  
Lindsey E. Lopes ◽  
Alexander M. van der Linden ◽  
David M. Raizen
Keyword(s):  
Histone Deacetylase ◽  
Sensory Neurons ◽  
Metabolic Regulation ◽  
Energy Homeostasis ◽  
Energy Charge ◽  
Cellular Energy ◽  
C Elegans ◽  
Atp Levels ◽  
Energy Stores ◽  
Fat Stores

ABSTRACTMany lines of evidence point to links between sleep regulation and energy homeostasis, but mechanisms underlying these connections are unknown. During C. elegans sleep, energetic stores are allocated to non-neural tasks with a resultant drop in the overall fat stores and energy charge. Mutants lacking KIN-29, the C. elegans homolog of a mammalian Salt-Inducible Kinase (SIK) that signals sleep pressure, have low ATP levels despite high fat stores, indicating a defective response to cellular energy deficits. Liberating energy stores corrects adiposity and sleep defects of kin-29 mutants. kin-29 sleep and energy homeostasis roles map to a small number of sensory neurons that act upstream of fat regulation as well as of central sleep-controlling neurons, suggesting hierarchical somatic/neural interactions regulating sleep and energy homeostasis. Genetic interaction between kin-29 and the histone deacetylase hda-4 coupled with subcellular localization studies indicate that KIN-29 acts in the nucleus to regulate sleep. We propose that KIN-29/SIK acts in nuclei of sensory neuroendocrine cells to transduce low cellular energy charge into the mobilization of energy stores, which in turn promotes sleep.HighlightsSleep is associated with fat mobilization and low ATP levelsMetabolic regulation of sleep requires the salt-induced kinase (SIK) homolog KIN-29KIN-29 acts in sensory neurons upstream of sleep-promoting neuronsNuclear localization of KIN-29 is required for the metabolic regulation of sleepA type 2 histone deacetylase acts down stream of KIN-29 in the regulation of sleep.Liberation of energy from fat-storage cells promotes sleep.Beta-oxidation promotes sleep.

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