ABSTRACT
The health of an organism is orchestrated by a multitude of molecular and biochemical networks responsible for ensuring homeostasis within cells and tissues. However, upon aging, a progressive failure in the maintenance of this homeostatic balance occurs in response to a variety of endogenous and environmental stresses, allowing the accumulation of damage, the physiological decline of individual tissues, and susceptibility to diseases. What are the molecular and cellular signaling events that control the aging process and how can this knowledge help design therapeutic strategies to combat age-associated diseases? Here we provide a comprehensive overview of the evolutionarily conserved biological processes that alter the rate of aging and discuss their link to disease prevention and the extension of healthy life span.
Subject(s)
DNA Damage , Longevity/genetics , Proteostasis Deficiencies/genetics , Signal Transduction , Telomere Shortening , AMP-Activated Protein Kinases/genetics , AMP-Activated Protein Kinases/metabolism , Animals , Caloric Restriction , Epigenesis, Genetic , Homeostasis/genetics , Humans , Inflammation , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/metabolism , Mitochondria/metabolism , Oxidative Stress , Proteostasis Deficiencies/metabolism , Proteostasis Deficiencies/pathology , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolismABSTRACT
Defects in mitochondrial metabolism have been increasingly linked with age-onset protein-misfolding diseases such as Alzheimer's, Parkinson's, and Huntington's. In response to protein-folding stress, compartment-specific unfolded protein responses (UPRs) within the ER, mitochondria, and cytosol work in parallel to ensure cellular protein homeostasis. While perturbation of individual compartments can make other compartments more susceptible to protein stress, the cellular conditions that trigger cross-communication between the individual UPRs remain poorly understood. We have uncovered a conserved, robust mechanism linking mitochondrial protein homeostasis and the cytosolic folding environment through changes in lipid homeostasis. Metabolic restructuring caused by mitochondrial stress or small-molecule activators trigger changes in gene expression coordinated uniquely by both the mitochondrial and cytosolic UPRs, protecting the cell from disease-associated proteins. Our data suggest an intricate and unique system of communication between UPRs in response to metabolic changes that could unveil new targets for diseases of protein misfolding.
Subject(s)
Cytosol/physiology , Heat-Shock Response/physiology , Lipids/biosynthesis , Mitochondria/physiology , Unfolded Protein Response/physiology , Animals , Caenorhabditis elegans/genetics , Caenorhabditis elegans/metabolism , Cell Line , Gene Expression Regulation , Gene Knockdown Techniques , Heat-Shock Proteins/genetics , Homeostasis , Humans , Lipid Metabolism/genetics , Mitochondrial Proteins/metabolism , Molecular Chaperones/genetics , Protein FoldingABSTRACT
The sensation of pain is associated with increased mortality, but it is unknown whether pain perception can directly affect aging. We find that mice lacking TRPV1 pain receptors are long-lived, displaying a youthful metabolic profile at old age. Loss of TRPV1 inactivates a calcium-signaling cascade that ends in the nuclear exclusion of the CREB-regulated transcriptional coactivator CRTC1 within pain sensory neurons originating from the spinal cord. In long-lived TRPV1 knockout mice, CRTC1 nuclear exclusion decreases production of the neuropeptide CGRP from sensory endings innervating the pancreatic islets, subsequently promoting insulin secretion and metabolic health. In contrast, CGRP homeostasis is disrupted with age in wild-type mice, resulting in metabolic decline. We show that pharmacologic inactivation of CGRP receptors in old wild-type animals can restore metabolic health. These data suggest that ablation of select pain sensory receptors or the inhibition of CGRP are associated with increased metabolic health and control longevity.
Subject(s)
Longevity , Signal Transduction , TRPV Cation Channels/metabolism , Animals , CREB-Binding Protein/metabolism , Caenorhabditis elegans , Cells, Cultured , Diet , Female , Insulin/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mutation , Neurons/metabolism , Nociceptors/metabolism , TRPV Cation Channels/genetics , Transcription Factors/metabolismABSTRACT
The double-stranded RNA-dependent protein kinase activating protein (PACT), an RNA-binding protein that is part of the RNA-induced silencing complex, plays a key role in miR-mediated translational repression. Previous studies showed that PACT regulates the expression of various miRs, selects the miR strand to be loaded onto RNA-induced silencing complex, and determines proper miR length. Apart from PACT's role in mediating the antiviral response in immune cells, what PACT does in other cell types is unknown. Strikingly, it has also been shown that cold exposure leads to marked downregulation of PACT protein in mouse brown adipose tissue (BAT), where mitochondrial biogenesis and metabolism play a central role. Here, we show that PACT establishes a posttranscriptional brake on mitochondrial biogenesis (mitobiogenesis) by promoting the maturation of miR-181c, a key suppressor of mitobiogenesis that has been shown to target mitochondrial complex IV subunit I (Mtco1) and sirtuin 1 (Sirt1). Consistently, we found that a partial reduction in PACT expression is sufficient to enhance mitobiogenesis in brown adipocytes in culture as well as during BAT activation in mice. In conclusion, we demonstrate an unexpected role for PACT in the regulation of mitochondrial biogenesis and energetics in cells and BAT.
Subject(s)
Adipose Tissue, Brown , MicroRNAs , Mitochondria , Organelle Biogenesis , RNA-Binding Proteins , Adipose Tissue, Brown/metabolism , Animals , Electron Transport Complex I/metabolism , Mice , MicroRNAs/genetics , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , RNA-Induced Silencing Complex/metabolismABSTRACT
The recognition of sensory signals from within the body (interoceptive) and from the external environment (exteroceptive), along with the integration of these cues by the central nervous system, plays a crucial role in maintaining metabolic balance. This orchestration is vital for regulating processes related to both food intake and energy expenditure. Animal model studies indicate that manipulating specific populations of neurons in the central nervous system which influence these processes can effectively modify energy balance. This body of work presents an opportunity for the development of innovative weight loss therapies for the treatment of obesity and type 2 diabetes. In this overview, we delve into the sensory cues and the neuronal populations responsible for their integration, exploring their potential in the development of weight loss treatments for obesity and type 2 diabetes. This article is the first in a series of Perspectives that report on research funded by the American Diabetes Association Pathway to Stop Diabetes program.
Subject(s)
Diabetes Mellitus, Type 2 , Animals , Diabetes Mellitus, Type 2/therapy , Thermogenesis/physiology , Obesity/therapy , Obesity/metabolism , Brain/metabolism , Energy Metabolism/physiology , Weight LossABSTRACT
Olfactory cues are vital for prey animals like rodents to perceive and evade predators. Stress-induced hyperthermia, via brown adipose tissue (BAT) thermogenesis, boosts physical performance and facilitates escape. However, many aspects of this response, including thermogenic control and sex-specific effects, remain enigmatic. Our study unveils that the predator odor trimethylthiazoline (TMT) elicits BAT thermogenesis, suppresses feeding, and drives glucocorticoid release in female mice. Chemogenetic stimulation of olfactory bulb (OB) mitral cells recapitulates the thermogenic output of this response and associated stress hormone corticosterone release in female mice. Neuronal projections from OB to medial amygdala (MeA) and dorsomedial hypothalamus (DMH) exhibit female-specific cFos activity toward odors. Cell sorting and single-cell RNA-sequencing of DMH identify cholecystokinin (CCK)-expressing neurons as recipients of predator odor cues. Chemogenetic manipulation and neuronal silencing of DMHCCK neurons further implicate these neurons in the propagation of predator odor-associated thermogenesis and food intake suppression, highlighting their role in female stress-induced hyperthermia.
Subject(s)
Cholecystokinin , Smell , Male , Mice , Female , Animals , Thermogenesis/physiology , Neurons/physiology , HypothalamusABSTRACT
BACKGROUND: Previously, we found low-carbohydrate diets slowed prostate cancer (PC) growth and increased survival vs. a Western diet in mice, by inhibiting the insulin/IGF-1 axis. Thus, we tested whether modifying carbohydrate quality to lower glycemic index (GI) without changing quantity results in similar benefits as with reduced quantity. METHODS: Male SCID mice injected with LAPC-4 cells were single-housed and randomized when their tumors reached 200 mm3 on average to a LoGI (48% carbohydrate kcal, from Hylon-VII) or HiGI Western diet (48% carbohydrate kcal, from sucrose). Body weight and tumor volume were measured weekly. Body composition was assessed 35 days after randomization. Blood glucose and serum insulin, IGF-1 and IGFBP3 were measured at study end when tumor volumes reached 800 mm3. We analyzed gene expression of mice tumors by RNA-sequencing and human tumors using the Prostate Cancer Transcriptome Atlas. RESULTS: There were no significant differences in tumor volume (P > 0.05), tumor proliferation (P = 0.29), and overall survival (P = 0.15) between groups. At 35 days after randomization, the LoGI group had 30% lower body fat (P = 0.007) despite similar body weight (P = 0.58). At sacrifice, LoGI mice had smaller livers (P < 0.001) and lower glucose (P = 0.15), insulin (P = 0.11), IGF-1 (P = 0.07) and IGF-1:IGFBP3 ratio (P = 0.05), and higher IGFBP3 (P = 0.09) vs. HiGI, although none of these metabolic differences reached statistical significance. We observed differential gene expression and pathway enrichment in mice tumors by diet. The most upregulated and downregulated gene in the LoGI group showed expression patterns more closely resembling expression in human benign prostate tissue vs. PC. CONCLUSIONS: In this single mouse xenograft model, consuming a low GI diet did not delay PC growth or survival vs. a high GI diet despite suggestions of decreased activation of the insulin/IGF-1 pathway. These data suggest that improving carbohydrate quality alone while consuming a high carbohydrate diet may not effectively slow PC growth.
ABSTRACT
The pathogenesis of atherosclerosis is defined by impaired lipid handling by macrophages which increases intracellular lipid accumulation. This dysregulation of macrophages triggers the accumulation of apoptotic cells and chronic inflammation which contributes to disease progression. We previously reported that mice with increased macrophage-specific angiotensin-converting enzyme, termed ACE10/10 mice, resist atherosclerosis in an adeno-associated virus-proprotein convertase subtilisin/kexin type 9 (AAV-PCSK9)-induced model. This is due to increased lipid metabolism by macrophages which contributes to plaque resolution. However, the importance of ACE in peripheral blood monocytes, which are the primary precursors of lesional-infiltrating macrophages, is still unknown in atherosclerosis. Here, we show that the ACE-mediated metabolic phenotype is already triggered in peripheral blood circulating monocytes and that this functional modification is directly transferred to differentiated macrophages in ACE10/10 mice. We found that Ly-6Clo monocytes were increased in atherosclerotic ACE10/10 mice. The monocytes isolated from atherosclerotic ACE10/10 mice showed enhanced lipid metabolism, elevated mitochondrial activity, and increased adenosine triphosphate (ATP) levels which implies that ACE overexpression is already altered in atherosclerosis. Furthermore, we observed increased oxygen consumption (VO2), respiratory exchange ratio (RER), and spontaneous physical activity in ACE10/10 mice compared to WT mice in atherosclerotic conditions, indicating enhanced systemic energy consumption. Thus, ACE overexpression in myeloid lineage cells modifies the metabolic function of peripheral blood circulating monocytes which differentiate to macrophages and protect against atherosclerotic lesion progression due to better lipid metabolism.
Subject(s)
Atherosclerosis , Proprotein Convertase 9 , Animals , Mice , Atherosclerosis/pathology , Lipids , Myeloid Cells/pathologyABSTRACT
Olfactory perception guides daily decisions regarding food consumption, social interactions, and predator avoidance in all mammalian species. Volatile inputs, comprising odorants and pheromones, are relayed to the olfactory bulb (OB) from nasal sensory neurons cells and transferred to secondary processing regions within the brain. Olfaction has recently been shown to shape homeostatic and maladaptive processes of energy intake and expenditure through neuronal circuits involving the medial basal hypothalamus. Reciprocally, gastrointestinal hormones, such as ghrelin and leptin, the secretion of which depends on satiety and adiposity levels, might also influence olfactory sensitivity to alter food-seeking behaviors. Here, in addition to reviewing recent updates on identifying these neuronal networks, we also discuss how bidirectional neurocircuits existing between olfactory and energy processing centers can become dysregulated during obesity.
Subject(s)
Energy Metabolism , Olfactory Bulb , Animals , Energy Intake , Homeostasis , Humans , Mammals , Obesity , Olfactory Bulb/physiology , Smell/physiologyABSTRACT
Dopaminergic neuron degeneration in the midbrain plays a pivotal role in motor symptoms associated with Parkinson's disease. However, non-motor symptoms of Parkinson's disease and post-mortem histopathology confirm dysfunction in other brain areas, including the locus coeruleus and its associated neurotransmitter norepinephrine. Here, we investigate the role of central norepinephrine-producing neurons in Parkinson's disease by chronically stimulating catecholaminergic neurons in the locus coeruleus using chemogenetic manipulation. We show that norepinephrine neurons send complex axonal projections to the dopaminergic neurons in the substantia nigra, confirming physical communication between these regions. Furthermore, we demonstrate that increased activity of norepinephrine neurons is protective against dopaminergic neuronal depletion in human α-syn A53T missense mutation over-expressing mice and prevents motor dysfunction in these mice. Remarkably, elevated norepinephrine neurons action fails to alleviate α-synuclein aggregation and microgliosis in the substantia nigra suggesting the presence of an alternate neuroprotective mechanism. The beneficial effects of high norepinephrine neuron activity might be attributed to the action of norepinephrine on dopaminergic neurons, as recombinant norepinephrine treatment increased primary dopaminergic neuron cultures survival and neurite sprouting. Collectively, our results suggest a neuroprotective mechanism where noradrenergic neurons activity preserves the integrity of dopaminergic neurons, which prevents synucleinopathy-dependent loss of these cells.
Subject(s)
Parkinson Disease , Synucleinopathies , Animals , Disease Models, Animal , Dopaminergic Neurons/metabolism , Humans , Locus Coeruleus/metabolism , Mice , Mice, Transgenic , Norepinephrine/pharmacology , Norepinephrine/physiology , Parkinson Disease/pathology , Substantia Nigra/metabolism , alpha-Synuclein/genetics , alpha-Synuclein/metabolismABSTRACT
OBJECTIVES: Heat-sensory neurons from the dorsal root ganglia (DRG) play a pivotal role in detecting the cutaneous temperature and transmission of external signals to the brain, ensuring the maintenance of thermoregulation. However, whether these thermoreceptor neurons contribute to adaptive thermogenesis remains elusive. It is also unknown whether these neurons play a role in obesity and energy metabolism. METHODS: We used genetic ablation of heat-sensing neurons expressing calcitonin gene-related peptide α (CGRPα) to assess whole-body energy expenditure, weight gain, glucose tolerance, and insulin sensitivity in normal chow and high-fat diet-fed mice. Exvivo lipolysis and transcriptional characterization were combined with adipose tissue-clearing methods to visualize and probe the role of sensory nerves in adipose tissue. Adaptive thermogenesis was explored using infrared imaging of intrascapular brown adipose tissue (iBAT), tail, and core temperature upon various stimuli including diet, external temperature, and the cooling agent icilin. RESULTS: In this report, we show that genetic ablation of heat-sensing CGRPα neurons promotes resistance to weight gain upon high-fat diet (HFD) feeding and increases energy expenditure in mice. Mechanistically, we found that loss of CGRPα-expressing sensory neurons was associated with reduced lipid deposition in adipose tissue, enhanced expression of fatty acid oxidation genes, higher exvivo lipolysis in primary white adipocytes, and increased mitochondrial respiration from iBAT. Remarkably, mice lacking CGRPα sensory neurons manifested increased tail cutaneous vasoconstriction at room temperature. This exacerbated cold perception was not associated with reduced core temperature, suggesting that heat production and heat conservation mechanisms were engaged. Specific denervation of CGRPα neurons in intrascapular BAT did not contribute to the increased metabolic rate observed upon global sensory denervation. CONCLUSIONS: Taken together, these findings highlight an important role of cutaneous thermoreceptors in regulating energy metabolism by triggering counter-regulatory responses involving energy dissipation processes including lipid fuel utilization and cutaneous vasodilation.
Subject(s)
Calcitonin Gene-Related Peptide/genetics , Calcitonin Gene-Related Peptide/metabolism , Obesity/metabolism , Sensory Receptor Cells/metabolism , Thermogenesis/genetics , Thermogenesis/physiology , Adipose Tissue, Brown/metabolism , Adipose Tissue, Brown/pathology , Adipose Tissue, White/metabolism , Adipose Tissue, White/pathology , Animals , Body Temperature Regulation/genetics , Body Temperature Regulation/physiology , Cold Temperature , Diet, High-Fat/adverse effects , Energy Metabolism/genetics , Energy Metabolism/physiology , Female , Insulin Resistance , Lipolysis/genetics , Lipolysis/physiology , Male , Mice , NeuronsABSTRACT
OBJECTIVE: We sought to determine the extent of SARS-CoV-2 seroprevalence and the factors associated with seroprevalence across a diverse cohort of healthcare workers. DESIGN: Observational cohort study of healthcare workers, including SARS-CoV-2 serology testing and participant questionnaires. SETTINGS: A multisite healthcare delivery system located in Los Angeles County. PARTICIPANTS: A diverse and unselected population of adults (n=6062) employed in a multisite healthcare delivery system located in Los Angeles County, including individuals with direct patient contact and others with non-patient-oriented work functions. MAIN OUTCOMES: Using Bayesian and multivariate analyses, we estimated seroprevalence and factors associated with seropositivity and antibody levels, including pre-existing demographic and clinical characteristics; potential COVID-19 illness-related exposures; and symptoms consistent with COVID-19 infection. RESULTS: We observed a seroprevalence rate of 4.1%, with anosmia as the most prominently associated self-reported symptom (OR 11.04, p<0.001) in addition to fever (OR 2.02, p=0.002) and myalgias (OR 1.65, p=0.035). After adjusting for potential confounders, seroprevalence was also associated with Hispanic ethnicity (OR 1.98, p=0.001) and African-American race (OR 2.02, p=0.027) as well as contact with a COVID-19-diagnosed individual in the household (OR 5.73, p<0.001) or clinical work setting (OR 1.76, p=0.002). Importantly, African-American race and Hispanic ethnicity were associated with antibody positivity even after adjusting for personal COVID-19 diagnosis status, suggesting the contribution of unmeasured structural or societal factors. CONCLUSION AND RELEVANCE: The demographic factors associated with SARS-CoV-2 seroprevalence among our healthcare workers underscore the importance of exposure sources beyond the workplace. The size and diversity of our study population, combined with robust survey and modelling techniques, provide a vibrant picture of the demographic factors, exposures and symptoms that can identify individuals with susceptibility as well as potential to mount an immune response to COVID-19.
Subject(s)
Antibodies, Viral/blood , COVID-19/diagnosis , Health Personnel , Seroepidemiologic Studies , Adult , Bayes Theorem , COVID-19/immunology , COVID-19 Serological Testing , Cohort Studies , Cross-Sectional Studies , Female , Humans , Los Angeles/epidemiology , Male , Middle Aged , SARS-CoV-2/immunologyABSTRACT
Complex tasting divalent salts (CTDS) are present in our daily diet, contributing to multiple poorly understood taste sensations. CTDS evoking metallic, bitter, salty, and astringent sensations include the divalent salts of iron, zinc, copper, and magnesium. To identify pathways involved with the complex perception of the above salts, taste preference tests (two bottles, brief access) were performed in wild-type (WT) mice and in mice lacking (1) the T1R3 receptor, (2) TRPV1, the capsaicin receptor, or (3) the TRPM5 channel, the latter being necessary for the perception of sweet, bitter, and umami tasting stimuli. At low concentrations, FeSO(4) and ZnSO(4) were perceived as pleasant stimuli by WT mice, and this effect was fully reversed in TRPM5 knock-out mice. In contrast, MgSO(4) and CuSO(4) were aversive to WT mice, but for MgSO(4) the aversion was abolished in TRPM5 knock-out animals, and for CuSO(4), aversion decreased in both TRPV1- and TRPM5-deficient animals. Behavioral tests revealed that the T1R3 subunit of the sweet and umami receptors is implicated in the hedonically positive perception of FeSO(4) and ZnSO(4). For high concentrations of CTDS, the omission of TRPV1 reduced aversion. Imaging studies on heterologously expressed TRPM5 and TRPV1 channels are consistent with the behavioral experiments. Together, these results rationalize the complexity of metallic taste by showing that at low concentrations, compounds such as FeSO(4) and ZnSO(4) stimulate the gustatory system through the hedonically positive T1R3-TRPM5 pathway, and at higher concentrations, their aversion is mediated, in part, by the activation of TRPV1.
Subject(s)
Food Preferences/physiology , Salts , TRPM Cation Channels/physiology , TRPV Cation Channels/physiology , Taste/physiology , Animals , Capsaicin/pharmacology , Cell Line, Transformed , Choice Behavior/drug effects , Choice Behavior/physiology , Copper Sulfate/pharmacology , Dose-Response Relationship, Drug , Drinking Behavior/drug effects , Female , Ferrous Compounds/pharmacology , Food Preferences/drug effects , Gene Expression/drug effects , Humans , Linear Models , Magnesium Sulfate/pharmacology , Male , Membrane Potentials/drug effects , Membrane Potentials/physiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mutagenesis, Site-Directed/methods , Protein Binding/drug effects , Salts/pharmacology , TRPM Cation Channels/deficiency , TRPM Cation Channels/genetics , TRPV Cation Channels/deficiency , TRPV Cation Channels/genetics , Taste/drug effects , Taste/genetics , Transfection , Zinc Sulfate/pharmacologyABSTRACT
OBJECTIVE: Calcitonin Gene-Related Peptide α (CGRPα) is a multifunctional neuropeptide found in the central and peripheral nervous system with cardiovascular, nociceptive, and gastrointestinal activities. CGRPα has been linked to obesity and insulin secretion but the role of this circulating peptide in energy metabolism remains unclear. Here, we thought to utilize a monoclonal antibody against circulating CGRPα to assess its ability to improve glucose homeostasis in mouse models of hyperglycemia and diabetes. METHODS: We examined the outcome of anti-CGRPα treatment in mouse models of diabetes and diet-induced obesity, using db/db mice, Streptozotocin (STZ) treatment to eliminate pancreatic islets, and high fat diet-fed mice. We also correlated these data with application of recombinant CGRPα peptide on cultured mature adipocytes to measure its impact on mitochondrial bioenergetics and fatty acid oxidation. Furthermore, we applied recombinant CGRPα to primary islets to measure glucose-stimulated insulin secretion (GSIS) and gene expression. RESULTS: BL6-db diabetic mice receiving anti-CGRPα treatment manifested weight loss, reduced adiposity, improved glucose tolerance, insulin sensitivity, GSIS and reduced pathology in adipose tissue and liver. Anti-CGRPα failed to modulate weight or glucose homeostasis in STZ-treated animals. High fat diet-fed mice showed reduced adiposity but no benefit on glucose homeostasis. Considering these findings, we postulated that CGRPα may have dual effects on adipocytes to promote lipid utilization while acting on pancreatic ß-cells to modulate insulin secretion. Analysis of CGRPα in the pancreas showed that the peptide localized to insulin-positive cells and perivascular nerves surrounding islets. Ex-vivo analysis of pancreatic islets determined that CGRPα blocked GSIS and reduced insulin-2 gene expression. Mechanistical analysis revealed that recombinant CGRPα was able to reduce glycolytic capacity as well as fatty acid oxidation in primary white adipocytes. CONCLUSIONS: These results establish a multifaceted role in energy metabolism for circulating CGRPα, with the ability to modulate thermogenic pathways in adipose tissue, as well as pancreatic ß-cell dependent insulin secretion. Reducing circulating CGRPα levels with monoclonal therapy presents therapeutic potential for type 2 diabetes as shown in BL6-db/db mice but has reduced potential for models of hyperglycemia resulting from loss of ß-cells (STZ treatment).
ABSTRACT
The seminal experiments of Ivan Petrovich Pavlov set the stage for an understanding of the physiological concomitants of appetite and feeding behavior. His findings, from careful and creative experimentation, have been uncontested for over a century. One of Pavlov's most fundamental observations was that activation of salivary, gastric and pancreatic secretions during feeding and sham-feeding, precedes entry of food into the mouth, generating signals to the brain from various sensory pathways. Pavlov referred to this as the "psychic" phase of digestion. However, quite surprisingly, he did not attempt to isolate any single sensory system as the main driver of this phenomenon. Herein we revisit Pavlov's findings and hypothesize that the evolutionarily-important sense of smell is the pathway most-likely determinant of feeding behavior in mammals. Substantial understandings of olfactory receptors and their neural pathways in the central nervous system have emerged over the past decade. Neurogenic signals, working in concert with hormonal inputs are described, illustrating the ways in which sense of smell determines food-seeking and food-preference. Additionally, we describe how sense of smell affects metabolic pathways relevant to energy metabolism, hunger and satiety as well as a broad range of human behaviors, thereby reinforcing its central biological role in mammals. Intriguing possibilities for future research, based upon this hypothesis, are raised.
ABSTRACT
Artificial sweeteners such as saccharin, aspartame, acesulfame-K, and cyclamate produce at high concentrations an unpleasant after-taste that is generally attributed to bitter and metallic taste sensations. To identify receptors involved with the complex perception of the above compounds, preference tests were performed in wild-type mice and mice lacking the TRPV1 channel or the T1R3 receptor, the latter being necessary for the perception of sweet taste. The sweeteners, including cyclamate, displayed a biphasic response profile, with the T1R3 mediated component implicated in preference. At high concentrations imparting off-taste, omission of TRPV1 reduced aversion. In a heterologous expression system the Y511A point mutation in the vanilloid pocket of TRPV1 did not affect saccharin and aspartame responses but abolished cyclamate and acesulfame-K activities. The results rationalize artificial sweetener tastes and off-tastes by showing that at low concentrations, these molecules stimulate the gustatory system through the hedonically positive T1R3 pathway, and at higher concentrations, their aversion is partly mediated by TRPV1.
Subject(s)
Receptors, G-Protein-Coupled/physiology , Sweetening Agents/metabolism , TRPV Cation Channels/physiology , Taste/physiology , Animals , Humans , Mice , Mice, Knockout , Receptors, G-Protein-Coupled/agonists , Receptors, G-Protein-Coupled/genetics , Sweetening Agents/pharmacology , TRPV Cation Channels/agonists , TRPV Cation Channels/genetics , Taste/drug effects , Taste/geneticsABSTRACT
Preservation of mitochondrial function, which is dependent on mitochondrial homeostasis (biogenesis, dynamics, disposal/recycling), is critical for maintenance of skeletal muscle function. Skeletal muscle performance declines upon aging (sarcopenia) and is accompanied by decreased mitochondrial function in fast-glycolytic muscles. Oxidative metabolism promotes mitochondrial homeostasis, so we investigated whether mitochondrial function is preserved in oxidative muscles. We compared tibialis anterior (predominantly glycolytic) and soleus (oxidative) muscles from young (3 mo) and old (28-29 mo) C57BL/6J mice. Throughout life, the soleus remained more oxidative than the tibialis anterior and expressed higher levels of markers of mitochondrial biogenesis, fission/fusion and autophagy. The respiratory capacity of mitochondria isolated from the tibialis anterior, but not the soleus, declined upon aging. The soleus and tibialis anterior exhibited similar aging-associated changes in mitochondrial biogenesis, fission/fusion, disposal and autophagy marker expression, but opposite changes in fiber composition: the most oxidative fibers declined in the tibialis anterior, while the more glycolytic fibers declined in the soleus. In conclusion, oxidative muscles are protected from mitochondrial aging, probably due to better mitochondrial homeostasis ab initio and aging-associated changes in fiber composition. Exercise training aimed at enriching oxidative fibers may be valuable in preventing mitochondria-related aging and its contribution to sarcopenia.
Subject(s)
Mitochondria, Muscle/physiology , Muscle, Skeletal/physiology , Oxygen Consumption/physiology , Aging , Animals , DNA, Mitochondrial/genetics , Homeostasis , Male , Mice , Mice, Inbred C57BL , Muscle Fibers, Skeletal/metabolism , Mutation , Oxidation-Reduction , Oxidative Stress , Physical Conditioning, AnimalABSTRACT
Olfactory inputs help coordinate food appreciation and selection, but their role in systemic physiology and energy balance is poorly understood. Here we demonstrate that mice upon conditional ablation of mature olfactory sensory neurons (OSNs) are resistant to diet-induced obesity accompanied by increased thermogenesis in brown and inguinal fat depots. Acute loss of smell perception after obesity onset not only abrogated further weight gain but also improved fat mass and insulin resistance. Reduced olfactory input stimulates sympathetic nerve activity, resulting in activation of ß-adrenergic receptors on white and brown adipocytes to promote lipolysis. Conversely, conditional ablation of the IGF1 receptor in OSNs enhances olfactory performance in mice and leads to increased adiposity and insulin resistance. These findings unravel a new bidirectional function for the olfactory system in controlling energy homeostasis in response to sensory and hormonal signals.
Subject(s)
Obesity/metabolism , Obesity/physiopathology , Olfactory Receptor Neurons/metabolism , Smell , Thermogenesis , Adipose Tissue, Brown/metabolism , Adipose Tissue, Brown/physiopathology , Animals , Diet, High-Fat/adverse effects , Energy Metabolism , Insulin Resistance , Insulin-Like Growth Factor I/metabolism , Lipolysis , Mice , Obesity/etiology , Olfactory Receptor Neurons/pathology , Receptors, Adrenergic, beta/metabolism , Weight GainABSTRACT
Sensory perception comprises gustatory (taste) and olfactory (smell) modalities as well as somatosensory (pain, heat, and tactile mechanosensory) inputs, which are detected by a multitude of sensory receptors. These sensory receptors are contained in specialized ciliated neurons where they detect changes in environmental conditions and participate in behavioral decisions ranging from food choice to avoiding harmful conditions, thus insuring basic survival in metazoans. Recent genetic studies, however, indicate that sensory perception plays additional physiological functions, notably influencing energy homeostatic processes and longevity through neuronal circuits originating from sensory tissues. Here we review how these findings are redefining metabolic signaling and establish a prominent role of sensory neuroendocrine processes in controlling health span and lifespan, with a goal of translating this knowledge towards managing age-associated diseases.