Aging disrupts physiological homeostasis, impairing thermoregulation, metabolism, and water balance, but the underlying neural mechanisms remain unclear. Here, we identify arginine vasopressin (AVP) neurons in the supraoptic nucleus (SON) of the hypothalamus as a critical driver of these changes. Using single-nucleus RNA-sequencing of the anterior hypothalamus in young and aged mice, we found Avp to be one of the most upregulated neuronal transcripts with age. Aged SON-AVP neurons displayed enlarged size and heightened excitability, features consistent with hyperactivity. Functionally, chemogenetic activation of SON-AVP neurons in young mice reproduced aging-associated phenotypes including hypothermia, reduced energy expenditure, and suppressed water intake. Conversely, knockdown of Avp in the SON of aged mice restored water balance, partially improved thermoregulation and systemic metabolism. Pharmacological inhibition of AVP receptors revealed that neuroendocrine release of AVP drives homeostatic deficits, with distinct roles for V1A and V2 receptors. Senolytic drug treatment improved systemic metabolism and reduced inflammaging but does not rescue hypothalamic AVP dysfunction, underscoring a brain autonomous mechanism of age-related physiological failure. Together, our findings establish SON-AVP neuronal hyperactivity as a driver of impaired homeostasis with age and suggest that targeted modulation of neuroendocrine AVP signaling may offer a therapeutic strategy to alleviate age-associated water balance defects.

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. Article Highlights

A new study finds that capillary vessels become obstructed in diabetes and that their dysfunction may cause microvascular damage and lead to cognitive deficits. Such obstruction is independent of the elevated blood sugar found in diabetes and is triggered by elevated interleukin-10 cytokine signalling in cerebral blood vessel endothelial cells.

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.

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 mm 3 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 mm 3 . 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.

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.

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.

Abstract When detecting danger signals, animals exhibit adaptive changes in physiology and behavior aimed at increasing survival. In small prey animals, such as rodents, olfactory information plays a fundamental role in the perception of their environment and predator avoidance. Exposure to predation has been associated with reduced fatness in male rodents, but whether similar responses exist in both sexes is poorly understood. Exactly how the nervous system regulates weight in the context of danger perception remains unknown. Here we identify a sex-specific response leading to increased energy expenditure and elevated corticosterone in female mice exposed to predator smell or global stimulation of mitral and tufted cells of the olfactory bulb (OB). This response is absent in male mice and is not attenuated by gonadectomy in females. A population of neurons in the dorsomedial hypothalamus (DMH), selectively activated by aversive olfactory signals also receives polysynaptic afferents from mitral and tufted cells of the main OB (MOB). Cell sorting of projection neurons in the DMH receiving olfactory inputs and single-nucleus RNA-sequencing identify cholecystokinin (Cck)-expressing neurons as putative recipients of olfactory inputs. Chemogenetic stimulation of DMHCCK neurons recapitulates the effects of aversive olfactory stimulation on female energy expenditure. Taken together, our results suggest the existence of a female heightened stress reaction recruiting DMHCCK neurons to promote high energy utilization.

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.

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.

Heat-sensory neurons arising from the dorsal root ganglia (DRG) play a pivotal role in the detection of cutaneous temperature and transmission of external signals to the brain, ensuring the maintenance of thermoregulation. However, whether these thermoreceptor neurons contribute to adaptive thermogenesis has remained elusive. We show that genetic ablation of heat sensing Calcitonin Gene-Related Peptide α (CGRPα) neurons promotes resistance to weight gain upon high fat diet (HFD) feeding and increases energy expenditure in mice. Mechanistically, we find that loss of CGRPα-expressing sensory neurons is associated with reduced lipid deposition in adipose tissue, enhanced expression of fatty-acid oxidation genes, higher ex-vivo lipolysis in primary white adipocytes and enhanced mitochondrial respiration from iBAT. Remarkably, mice lacking CGRPα sensory neurons manifest 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 are engaged. Specific denervation of CGRPα neurons in intrascapular BAT did not contribute to the increased metabolic rate observed upon global sensory denervation. Taken together, these findings highlight an important role for cutaneous thermoreceptors in regulating energy metabolism, by triggering counter-regulatory responses involving energy dissipation processes including lipid fuel utilization and cutaneous vasodilation. Disclosure C. Riera: None. Funding American Diabetes Association/Pathway to Stop Diabetes (1-15-INI-12 to C.R.)

Sensory neurons arising from the dorsal root ganglia play a pivotal role in thermoregulation through the detection of cutaneous temperature and transmission of sensory signals to the brain. However, the functional significance of sensory perception in thermogenesis and weight loss has remained elusive. Here, we show that genetic ablation of heat sensing neurons containing Calcitonin Gene-Related Peptide (CGRPα) promotes resistance to weight gain upon high fat diet (HFD) feeding and drives a thermogenic program in brown and white adipose tissues. Remarkably, mice lacking CGRPα-expressing sensory neurons feel colder when challenged with cooling stimuli and their brown fat displays increased energy utilization during cold and HFD challenges. As these neurons are peptidergic, we also investigated the role of the CGRPα secreted peptide in this process. Depletion of CGRPα with a monoclonal antibody leads to a lesser weight loss than full neural depletion on HFD and partially recapitulates the increased energy expenditure and brown fat thermogenic profile observed with sensory ablation. Mechanistically, recombinant CGRPα impaired glycolysis and reduced fatty acid oxidation in cultured cells. Collectively, our results suggest that CGRPα-expressing sensory neurons are the first step to regulate adaptive thermogenesis in brown adipose tissue by detecting alterations in environmental temperatures. These neural processes have the dual ability to both influence central regulation of adrenergic stimulation of thermogenesis and to release peptidergic signals inhibiting fuel consumption in adipocytes.

Olfactory inputs are important for hedonic evaluation of food, resulting in food choice and possible consumption. The hypothalamus is a master regulator of whole-body energy homeostasis, integrating internal and external stimuli to modulate energy intake and expenditure accordingly. However, how the hypothalamus adjusts circuits regulating energy homeostasis depending on external stimuli, such as smell, remains an intriguing mystery. Here, we determined the role of olfactory inputs on energy homeostasis by using chemogenetic approach and chemical ablation of OSN to inhibit or stimulate olfaction. Acute inhibition of olfaction changed gene expression of some key neuropeptides in hypothalamus in fasted and refed mice. Chronic silencing of mitral cells in OB promotes resistance to diet-induced obesity, mainly by decreasing food intake. Additionally, chemical ablation of mature OSNs decreases neuronal activity in olfactory cortex and in ARC suggesting that loss of smell, in addition to impacting olfactory pathways, also affects neuronal activity in the ARC, and therefore is likely to alter energy homeostasis. Acute stimulation of mitral cells layer in OB increases neuronal activity in ARC as well as dorsomedial hypothalamus (DMH). Observed increase in ARC neuronal activity is mainly due to activation of glutaminergic neurons. Acute stimulation of olfaction led to increased oxygen consumption and heat production, with no changes observed upon chronic stimulation. Further studies are required to determine specific neuronal cell types within the ARC and DMH that respond to inhibition/stimulation of olfaction and therefore modulating energy homeostasis. Disclosure C. Riera: None. Funding American Diabetes Association Pathway to Stop Diabetes (1-15-INI-12)

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 β-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 β-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 β-cells (STZ treatment).

The neuropeptide Calcitonin Gene-Related Peptide (CGRP) is a 37-amino acid peptide, with a wide-range of biological activities including vasodilation [1], neurogenic inflammation [1], immune function [2] and hypertension [3]. In addition to these various roles, it has also been heavily implicated in metabolic disease, with roles in feeding, energy dissipation processes and pancreatic β-cell insulin secretion. One of the most striking effects of delivering CGRP either by intraperitoneal or intracranial routes is an acute reduction of food intake and energy expenditure [4–7]. This important function has been linked to activation of brain parabrachial neurons which contain CGRP and acutely suppress feeding to cause starvation [8]. Remarkably, CGRP is present in both central and peripheral nervous systems, where it is likely to have different biological activities. Krahn et al. noted that intracranial CGRP delivery was more potent at inhibiting feeding compared to intraperitoneal route [5]. Moreover, whole-body deletion of mouse CGRPα increased food intake, but also led to a surprising resistance to weight gain on diet-induced obesity [9], suggesting that complementary effects on energy expenditure were being recruited to dissipate the additional calories ingested. These data highlight the need to scrutinize central and peripheral specificity of the CGRP peptide in energy balance.

ABSTRACTImportanceAntibody testing is important for understanding patterns of exposure and potential immunity to SARS-CoV-2. Prior data on seroprevalence have been subject to variations in selection of individuals and nature as well as timing of testing in relation to exposures.ObjectiveWe sought to determine the extent of SARS-CoV-2 seroprevalance and the factors associated with seroprevelance across a diverse cohort of healthcare workers.DesignObservational cohort study of healthcare workers, including SARS-CoV-2 serology testing and participant questionaires.ParticipantsA diverse and unselected population of adults (n=6,062) employed in a multi-site healthcare delivery system located in Los Angeles County, including individuals with direct patient contact and others with non-patient-oriented work functions.ExposureExposure and infection with the SARS-CoV-2 virus, as determined by seropositivity.Main OutcomesUsing Bayesian and multi-variate analyses, we estimated seroprevalence and factors associated with seropositivity and antibody titers, including pre-existing demographic and clinical characteristics; potential Covid-19 illness related exposures; and, symptoms consistent with Covid-19 infection.ResultsWe observed a seroprevalence rate of 4.1%, with anosmia as the most prominently associated self-reported symptom in addition to fever, dry cough, anorexia, and myalgias. After adjusting for potential confounders, pre-existing medical conditions were not associated with antibody positivity. However, seroprevalence was associated with younger age, Hispanic ethnicity, and African-American race, as well as presence of either a personal or household member having a prior diagnosis of Covid-19. 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 societally factors. Notably, number of people, or children, in the home was not associated with antibody positivity.Conclusion and RelevanceThe 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 modeling 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.Key PointsQuestionWhat is the SARS-CoV-2 IgG seroprevalence rate across a large and diverse healthcare worker population, and which clinical, envionrmental, and symptom-based measures are associated with seropositivity?FindingsWe observed a seroprevalence rate of 4.1%. Adjusting for potential confounders, seropositivity was associated with younger age, Hispanic ethnicity, African-American race, and the symptom of anosmia, while not significantly associated with any pre-existing medical conditions.MeaningFactors associated with SARS-CoV-2 seroprevalence among our healthcare workers underscore the importance of exposure sources beyond the workplace.

AbstractOf individuals with SARS-CoV-2 IgG antibody testing performed, those who contemporaneously experienced a cluster of Covid-19 relevant symptoms in the 1-2 months preceding the antibody assay were more likely to test positive whereas those who experienced the symptom clustering in the prior 3-6 months were more likely to test negative. These findings suggest that antibodies likely wane over a period of months, particularly in relation to the timing of symptoms.

Olfactory inputs are important for hedonic evaluation of food, resulting in food choice and possible consumption. Olfactory acuity is determined by the feeding status, with hunger enhancing smell and food seeking behavior, whereas satiety suppresses olfaction and promotes energy expenditure. Efforts to understand the cellular basis of food intake and energy expenditure revealed the crucial role of the hypothalamus as a master regulator of whole-body energy homeostasis, integrating internal and external stimuli to modulate energy intake and expenditure accordingly. However, how the hypothalamus adjusts circuits regulating energy homeostasis depending on external stimuli, such as smell, remains an intriguing mystery. Our previous work revealed that ablation of olfactory sensory neurons (OSNs) stimulates hypothalamic-driven autonomic tone and promotes catabolic pathways, enhancing thermogenesis in adipose tissue. These findings unravel a new function for the olfactory system in controlling energy homeostasis in response to sensory signals. Here, we analyzed neural circuits connecting olfaction and hypothalamus and determined the role of olfactory inputs on energy homeostasis. To identify neural circuits linking olfactory and hypothalamic neurons, we conducted anterograde viral tracing from mitral cell layer in the main olfactory bulb (MOB) in Tbx21-Cre mice and retrograde viral tracing from pro-opiomelanoctin (POMC)- and agouti-related protein (AgRP)-expressing hypothalamic neurons in POMC-Cre and AgRP-IRES-Cre mice using Cre-dependent helper virus and modified rabies virus. Additionally, we used chemical ablation of mature OSNs and chemogenetic silencing of mitral cell layer neurons to determine the effect of olfaction on energy homeostasis. Our data suggest that piriform cortex (PC)-amygdala (Amy)-arcuate nucleus of hypothalamus (ARC) is one of the plausible circuits responsible for transferring signals from MOB to the hypothalamus. Disclosure C. Riera: None. Funding American Diabetes Association/Pathway to Stop Diabetes (1-15-INI-12)

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.