| AMP-activated kinase |
Key sensor and mediator of energy homeostasis. Activated by a relative increase in the AMP:ATP ratio, changes in nutrient and metabolite concentrations, and other stressors. Modulates catabolic and anabolic pathways to promote ATP conservation and generation. Roles are well characterized in skeletal muscle and liver, where it influences diverse pathways including fatty acid, cholesterol and isoprenoid biosynthesis; fatty acid oxidation; hepatic glucose production; glucose transport; mitochondrial biogenesis; and protein synthesis. In adipocytes, modulates adipogenesis and inflammation in addition to metabolic pathways.
|
Widely expressed in brain where it plays a role in intracellular energy homeostasis. Regulates energy homeostasis at a whole-body level via activity within distinct neuronal subpopulations of the hypothalamus. Responsive to many hormonal signals and nutrient levels and, accordingly, impacts appetite and feeding behavior, metabolism, and circadian rhythms in order to promote a neutral energy balance. Modulates neural developmental processes, including neural progenitor cell proliferation, migration, maturation and neural network integration, as well as synaptic function and plasticity. Implicated in CNS stress responses and in β-amyloid metabolism and tau phosphorylation.
|
[76, 110] |
| Insulin |
Peptide hormone secreted by pancreatic β cells that is responsible for mediating glucose and lipid homeostasis. Inhibits hepatic glucose production, while stimulating cellular glucose uptake, glycogen and fatty acid synthesis, and cell growth and proliferation.
|
Acts as an endocrine and paracrine factor in brain (along with related peptides), with relatively high levels found in hypothalamus, hippocampus, cortex, olfactory bulb, and pituitary. Neurons ubiquitously express insulin receptors. Has anorexigenic effects on food intake and energy metabolism. Promotes neural development and cellular differentiation. Modulates learning and memory through effects on synaptic development and plasticity, including long-term potentiation and depression. Mediates neuronal survival, tau phosphorylation, β-amyloid metabolism, and responses to oxidative stress and ischemia.
|
[111] |
| Sirtuins |
Act as sensors for metabolic status and as modulators of energy-sensitive pathways. The metabolic cofactor, nicotinamide adenine dinucleotide is rate-limiting co-substrate for deacetylase activity. Roles have been studied in detail in tissues responsible for mediating energy homeostasis and include effects on glucose and lipid metabolism in the liver, insulin secretion in the pancreas, lipid storage and mobilization in adipose tissue, and the activity of circadian clocks in these tissues. Implicated in regulating mitochondrial biogenesis, inflammation, autophagy, senescence, apoptosis and cell viability, as well as other pathways. Molecular targets are diverse, but histone proteins are one particularly important set of targets that link activity with chromatin structure and epigenetic regulation.
|
Expressed throughout the brain, in specific regional, cellular, and subcellular patterns. Functions are context-specific and include mediation of neurogenesis, myelination, synaptic development, and circadian rhythms. Best-studied factor, SIRT1, is expressed in microglia and in neurons during neural development and adult life with high levels in the hypothalamus, cortex, hippocampus, and cerebellum. Hypothalamic SIRT1 activity may protect against dietary obesity and diabetes. SIRT2 is found in oligodendrocytes, where it plays a role in myelination and neuronal-glial interactions. SIRT5, a mitochondrial protein, is found selectively in layer II of the cortex. Activity seems to be neuroprotective in a range of neurodegenerative diseases and other neuropathological states.
|
[112, 113] |
