Olfaction under metabolic influences

Abstract

Recently published work and emerging research efforts have suggested that the olfactory system is intimately linked with the endocrine systems that regulate or modify energy balance. Although much attention has been focused on the parallels between taste transduction and neuroendocrine controls of digestion due to the novel discovery of taste receptors and molecular components shared by the tongue and gut, the equivalent body of knowledge that has accumulated for the olfactory system, has largely been overlooked. During regular cycles of food intake or disorders of endocrine function, olfaction is modulated in response to changing levels of various molecules, such as ghrelin, orexins, neuropeptide Y, insulin, leptin, and cholecystokinin. In view of the worldwide health concern regarding the rising incidence of diabetes, obesity, and related metabolic disorders, we present a comprehensive review that addresses the current knowledge of hormonal modulation of olfactory perception and how disruption of hormonal signaling in the olfactory system can affect energy homeostasis.

Figures

Table 1

Main molecules implicated in appetite regulation and expressed in the olfactory system.

Figure 1

A schematic representation of the broad expression of hormone-, peptide-, and energy-related receptors for the major metabolic factors in the olfactory system. The top of the schematic demonstrates cellular and subcellular distribution of factors in the olfactory muscosa; the bottom part demonstrates the same for the olfactory bulb. OSN = olfactory sensory neuron, IR = insulin receptor kinase, Ob-R = leptin receptor, OXR = orexin receptor, GLUT = glucose transporter, CB1 = cannabinoid receptor 1, SUS = sustentacular cells, NPY Y1 = neuropeptide Y receptor Y1, AdipoR = adiponectin receptor, CCK2R = cholecystokinin receptor 2, GHSR = ghrelin receptor, GLP-1R = glucagon-like protein receptor-1, sst-R = somatostatin receptor, MCH-R = melanin-concentrating hormone receptor, NMB-R = neuromedin B receptor, CRFR2 = corticotropin-releasing factor receptor-2.

Table 2

Comparative localization of orexigenic and anorexigenic signals in olfactory areas and the hypothalamus (+ = Present; – = Absent; and nd = Not Determined). OM = olfactory mucosa, OB = olfactory bulb, Hypo = hypothalamus, NPY = neuropeptide Y, MCH = melanin-concentrating hormone, CCK = cholecystokinin, NMB = neuromedin B, CRF = corticotropin-releasing factor, AA = amino acids.

Figure 2

A schematic representing the identity of a voltage-dependent potassium channel, Kv1.3, which is a substrate for insulin signaling in the OB. Kv1.3 is highly expressed in mitral neurons of the OB, where it carries a large proportion of voltage-gated outward currents (not shown) and mediates dampening of excitability by regulating action-potential timing and interspike interval (top left traces). Short-term regulation by insulin: Kv1.3 has multiple tyrosine (Y) residues (circles) that could serve as recognition motifs for tyrosine phosphorylation. Upon binding of the hormone insulin to the alpha subunits of the insulin receptor (IR) kinase (right side of schematic), multiple sites along the beta subunits (red circles) undergo autophosphorylation and the activated IR subsequently phosphorylates residues 111–113, 137, and 449 in the amino and carboxyl terminals of the Kv1.3 channel (red circles). As measured by recording under voltage-clamp conditions, phosphorylation causes a suppression of Kv1.3 via decreased open probability of the channel and via current clamp, it increases evoked action-potential frequency, spike train duration, and interspike interval while decreasing the pausing between spike clusters (top right traces). Obesity/Diabetes: Following diet-induced obesity (DIO) or chronic hyperglycemia of diabetes, the normal cycles of phosphorylation/dephosphorylation are imbalanced (black bar). Mice challenged with DIO exhibit mitral cell firing with irregular spike firing frequency, prominent spike adaptation, or partial amplitude. Application of acute insulin fails to increase spike frequency and Kv1.3 remains unphosphorylated (black circles)—both signs of insulin resistance. Bottom box: During natural cycles of feeding and fasting, olfactory physiology can be modulated through the rapid transport of insulin across the blood—brain barrier; but measured daily fluctuations in olfactory bulb (OB) and olfactory mucosal (OM) insulin are currently not reported.

Figure 3

Mechanisms by which regulatory metabolic factors can shift olfactory sensitivity to achieve nutritional homeostasis. Upon fasting or satiety, various peripheral molecules from the stomach, intestines, adipose tissue, and pancreas, among other peripheral localities, are up- or downregulated (bottom box). Through the blood, these signals target the hypothalamus (Hypo), olfactory bulb (OB), and olfactory mucosa (OM), among others. In turn, the hypothalamus releases metabolic factors to adapt food intake, which then maintains nutritional homeostasis. Both central and peripheral factors directly or indirectly target the olfactory system as a means to adapt it to the food foraging and the nutritional needs of the organism. Fasting increases olfactory sensitivity and associated olfactory-driven behaviors, whereas satiety counterbalances to decrease sensitivity and associated behaviors. MCH = melanin-concentrating hormone, NPY = neuropeptide Y, AgRP = agouti-related peptide, CRF = Corticotropin-releasing factor, POMC = proopiomelanocortin, CART = cocaine- and amphetamine-related transcript, OB = olfactory bulb, OM = olfactory mucosa, Hypo = hypothalamus, BBB = blood–brain barrier. Note: Size of font in bottom box reflects up- or downregulation of the metabolic factor during fasting or satiety.

Figure 4

Diagram of the centrifugal and efferent projections of the olfactory bulb. Black arrows indicate efferent projections and double-headed black arrows indicate two-way communication. Grey arrows indicate centrifugal input to the olfactory bulb. AOB = accessory olfactory bulb, AON = anterior olfactory nucleus, BNST = bed nucleus of the stria terminalis, DEPN = dorsal endopiriform nucleus, GP = globus pallidus, Hab = habenula, HLDBB = horizontal limb of the diagonal band of Broca, LC = locus coeruleus, MB = mammillary bodies, Raphe = dorsal and medial raphe nuclei, SS nigra = substantia nigra, SCN = suprachiasmatic nucleus, TT = taenia tecta, VTA = ventral tegmental area. Modified from Kelly, Wrynn, and Leonard (1997) and Krout et al. (2002).

Table 3

Olfactory disruption and metabolic disorders. Not accessed (NA), significantly decreased compared with control (↓), significantly increased compared with control (↑), not significantly different compared with control (=), Cross Cultural Smell Identification Test (CC-SIT), University of Pennsylvania Smell Identification Test (UPSIT), Odor Identification Test (OIT), Odor Detection Test (ODT), and Scandinavian Odor Identification Test (SOIT).