The traditional function of the olfactory system is to sense the external chemical world. Odors are inhaled directly into the nose following an orthonasal pathway, or come from the back part of the mouth following a retronasal pathway. Both pathways lead odors to the posterior part of the nasal cavity. Odors bind to protein receptors located in the ciliary membrane of olfactory sensory neurons (OSNs) within the olfactory epithelium (OE). Each OSN expresses only one type of olfactory receptor (Malnic et al., 1999; Serizawa et al., 2003). Odor/receptor association selectively activates OSNs in the OE. All OSNs expressing the same odorant receptor project their axons to one or two olfactory bulb (OB) glomeruli where OSN axons synapse with the dendrites of mitral cells (MCs); the second order olfactory neurons (Ressler et al., 1994; Vassar et al., 1994; Breer et al., 2006). The electrical signal is then transmitted to neuronal networks in the piriform cortex (PC). Olfaction thereby informs the central nervous system in real time about the chemical composition of the external environment prior to any visual or tactile information. This event allows the animal to anticipate and rapidly adapt its behavior when seeking food or when engaging in social or sexual behavior.

The hypothalamus is the main central actor in food intake regulation. Internal signals carried by the blood inform various central areas about the body's fuel availability, which in turn implement appropriate behavioral and metabolic responses to physiological requirements. Orexigenic and anorexigenic signals, respectively, stimulate or inhibit food intake by modulating neuronal activity of hypothalamic nuclei. During fasting, the hypothalamus induces food intake in response to nutrient scarcity and high level of ghrelin released by the stomach. Alternatively, the hypothalamus suppresses feeding behavior when it detects insulin secretion from the pancreas, leptin secretion from the adipose tissue, and nutrient abundance (Blouet and Schwartz, 2010; Berthoud, 2011). Interestingly, the olfactory system is also becoming widely considered as an active sensor of internal signaling (hormones, micronutrients availability). Olfactory structures like the OE, OB, and PC (Palouzier-Paulignan et al., 2012) express high levels of various hormone receptors (insulin, leptin, ghrelin, CCK) similar to that of the hypothalamus (Figure 1). When targeting their receptors, metabolic hormones modulate the electrical activity of olfactory networks (Fadool et al., 2000, 2011; Apelbaum et al., 2005; Hardy et al., 2005; Lacroix et al., 2008; Savigner et al., 2009; Kuczewski et al., 2014). OB neurons respond not only to peptides, but they also respond to glucose and express molecular hallmarks of glucose sensing cells (Tucker et al., 2010, 2013; Aimé et al., 2014; Al Koborssy et al., 2014; Kovach et al., 2016).

The metabolic sensing function of the OB is consistent with its high density of capillary network (Chaigneau et al., 2007) and its vascular properties. The blood brain barrier of the OB is not as tight as it is in the cerebral cortex or other brain regions (Ueno et al., 1991, 1996), indicating that blood-borne metabolic signals can enter the OB more easily than other brain regions. The permeable blood barrier facilitates transport of intravascular macromolecules, including nutrients and peripheral hormones, and their direct action on the OB. This enhanced permeability allows adaptation of olfactory perception to the physiological state: highly sensitive when the animal is fasted and needs to find food, and slightly sensitive when the animal is satiated (Aimé et al., 2007, 2012; Julliard et al., 2007; Prud'homme et al., 2009; Tong et al., 2011). Based upon its sensitivity to metabolic hormones and glucose availability, the olfactory system is proposed to be a metabolic sensor.

The present review provides an updated outlook of nutrient sensing in olfactory structures. We argue that in addition to being glucose-sensitive (Tucker et al., 2010, 2013; Aimé et al., 2014; Al Koborssy et al., 2014; Kovach et al., 2016) olfactory structures are sensors of amino acids (AAs) and potentially of fatty acid (FA) content of the internal medium.

Glucose is the primary metabolic substrate for the brain and a continuous supply of glucose is required for normal neuronal function (Mergenthaler et al., 2013). The brain accounts for 2% of the total body mass but requires 10 times more energy in the resting state compared to other energy consumption needs of the body (Mink et al., 1981; Molina and DiMaio, 2012). Glucose metabolism provides the fuel for physiological brain function through the generation of ATP that serves for the basic maintenance of cellular processes such as cytoskeletal dynamics, DNA repair, protein turnover, and growth. More specifically, during neuronal activation, the brain consumes a lot of energy in order to maintain the turnover of glutamate through metabolic neuron-astrocyte interactions (Magistretti and Allaman, 2015). Furthermore, 80% of total energy consumption fuels the Na⁺/K⁺ ATPase pump but <10% is used to recycle second messengers and neurotransmitters (Laughlin, 2001).

Glucose supply is critical for physiology, therefore a tight regulation between supply and demand is required. Several brain areas, such as the hypothalamus, brainstem, amygdala, septum, hippocampus, cortex, and OB contain glucose sensing neurons (Anand et al., 1964; Oomura et al., 1969; Ritter et al., 1981; Nakano et al., 1986; Shoji, 1992; Balfour et al., 2006; Tucker et al., 2013). These specialized neurons respond to local fluctuations in extracellular glucose levels, and modulate their mean firing rate accordingly. Glucose sensing neurons have been classified as “glucose-excited” (GE) or “glucose-inhibited” (GI) depending on whether they increase or decrease action potential frequency in response to extracellular glucose variations (McCrimmon, 2008; Gonzalez et al., 2009). GE and GI neurons integrate fluctuations in whole-body metabolic signals related to feeding behavior (Routh et al., 2007).

Several transporters, receptors, and ion channels are expressed in glucose sensing neurons of olfactory structures. Our laboratories and others have studied the role of the sodium-dependent glucose transporters (SGLTs), glucose transporters (GLUTs), potassium channels, and the insulin receptor (IR) in sensing glucose.

A variety of functions have been suggested for central glucose sensing neurons. Glucose sensing neurons are involved (i) in maintaining local energy requirements for synaptic transmission and (ii) in regulating whole body energy and glucose homeostasis. Glucose not only serves as a metabolic substrate but also alters neuronal activity linked to metabolism. Therefore, it's suggested that correct functioning of glucose sensing neurons would be essential to prevent metabolic disorders such as obesity and Type 2 diabetes mellitus but also stroke and other neurodegenerative disorders where neuronal energy supply is disrupted (Routh et al., 2007).

Central olfactory areas such as the OB and PC, have an expensive energy budget in terms of glucose metabolism, which is high during odor stimulation and increases further during coding and processing of olfactory information (Nawroth et al., 2007; Gire et al., 2013; Litaudon et al., 2017). Given that, we previously established a link between feeding states and olfactory performance, and adding the dynamic changes in GLUT4 expression, insulin levels, and the numerous metabolic hormones present in the OB, we suggest that glucose sensing neurons are keys regulators of metabolic-dependent olfactory behavior.

In rodents, the concentration, expression, and activity of several molecules involved in glucose-sensing in olfactory areas are not only modified with feeding behavior but they are also altered by metabolic pathologies and their subsequent nutritional imbalance. In the OB, insulin concentration and GLUT4 expression are feeding-dependent but SGLT1 and IR expression are not (Aimé et al., 2012; Al Koborssy et al., 2014). In commonly used rodent models of obesity and type 2 diabetes, insulin concentration is elevated and SGLT1 is upregulated in the OB. Moreover, IR expression is down regulated but GLUT4 remained affected in both the OB and PC (Livingston et al., 1993; Vannucci et al., 1998; Aimé et al., 2014). Rodent models of obesity further display increased olfactory sensitivity and discrimination (Aimé et al., 2014; Chelminski et al., 2017).

We propose that dysregulation of glucose sensing markers could induce an increase in olfactory sensitivity which could lead to hyperphagia and metabolic disorders. These results suggest that dysfunctional glucose sensing neurons in the OB could alter olfactory pathways crucial to the regulation of food intake.

Amino acids (AAs) play a key physiological role as building blocks of proteins. Proteins not only play a structural role in the organism but they are involved in various metabolic processes, including enzymatic reactions. Among the 20 AAs that serve for protein synthesis, 10 are referred to as the essential AAs because they are acquired only from the diet and cannot be stored in the body. AA supply requires numerous membrane transporters and receptors that are tissue specific. Each carrier recognizes several AAs having structural similarities. In this manner, one AA is transported inside cells through multiple carriers with overlapping specificities (Taylor, 2014).

AAs are key regulators of metabolism (Wu, 2009). Homeostatic regulation of AA level is necessary to adapt AA concentration (essential and non-essential AAs) to physiological body requirements. In order to maintain an adequate AA supply, the hypothalamus senses AA notably through leucine detection that signals AA abundance and directly regulates food intake. Leucine intake activates the mammalian target of rapamycin complex 1 (mTORC1) and inhibits AMP-activated protein kinase (AMPK) in order to regulate protein translation and to reduce food intake (Cota et al., 2006; Ropelle et al., 2008). Indeed, central injection of leucine in the ventromedial hypothalamic nucleus has an anorectic effect through activation of a hypothalamic-brainstem circuit (Cota et al., 2006; Blouet et al., 2009; Haissaguerre et al., 2014). The nature of ingested AAs is also a very important parameter. Animals reject diet imbalanced in essential AAs, and forage for food with adequate AA content (Morrison et al., 2012; Anthony and Gietzen, 2013).

In the brain, AAs sensing could also implicate membrane receptors of GPCR family including the taste heterodimer receptor family (T1R1/T1R3) (Hoon et al., 1999; Li et al., 2002; Nelson et al., 2002) and CasR receptors (Conigrave et al., 2002).

The olfactory system plays a major role in AA sensing. The most studied mechanism uses SLC transporters but some receptors might also be implicated.

Taken together, the fact that olfactory areas express transporters, receptors and intracellular molecules implicated in the regulation of AA content, strongly suggests that the OB and PC could play an important role in AAs sensing.

When it comes to AA sensing via transporter activation, two mechanisms coexist: one involves the mTORC1/AMPK pathway that detects AA availability and the second one involves GCN2 that specifically alerts when one or more essential AAs are insufficiently ingested. The hypothalamus is proposed to be the center for mTORC1/AMPK signaling (Cota et al., 2006; Ropelle et al., 2008; Hagglund et al., 2013) while the anterior part of PC (APC) utilizes GCN2. Leung's and Gietzen's teams have collected convergent data showing that the APC is a sensor of AAs imbalanced diet. Briefly, deficiency in one essential AA induces rapid rejection of the imbalanced diet (Leung et al., 1968; Koehnle et al., 2003; Gietzen and Aja, 2012; Morrison et al., 2012). This aversion disappears after APC lesion (Leung and Rogers, 1971) and persists after hypothalamus or OB injury (Leung and Rogers, 1970; Leung et al., 1972), which identifies the APC as the sensor of an AA imbalanced diet. Moreover, local injection of the deficient AA in the APC reduces food aversion by maintaining consumption of the imbalanced diet (Beverly et al., 1990; Russell et al., 2003). Accumulation of uncharged tRNA caused by AAs deficiency activates the GCN2 pathway (Hao et al., 2005; Rudell et al., 2011) and disinhibits the APC mainly through downregulation of GABA_A receptor and KCC2, also known as SLC12A5 transporter (Sharp et al., 2013). KCC2 is localized in GABAergic neurons in the OB and PC (Wang et al., 2005; Sharp et al., 2013). Glutamatergic pyramidal neurons in the APC would then send messages to feeding circuits, including the hypothalamus, in order to stop food intake (Gietzen and Magrum, 2001). Noteworthy is that mTORC1 is not involved here because behavioral rejection of the improper diet remains in the presence of rapamycin (Hao et al., 2010) (Figure 4A).

The role played by the APC in sensing AA deficiency is thus clear. However, sensing AA abundance via other olfactory structures has not been explored yet. It would be interesting to explore the possible implication of OB and/or PC in detecting AA abundancy and scarcity through mTORC1/AMPK pathways and through AA receptor activation.

Another sensor of AAs, Tas1R1, seems to be dependent on the feeding state when expressed in the hypothalamus. Tas1r1 levels increase following a 24-h food deprivation (Ren et al., 2009). Tas1r1 is highly expressed in the hypothalamus of obese and hyperglycemic ob/ob mice. The similarities between the nutrient sensing properties of the hypothalamus and that of the OB (Figure 1) prompt further investigation of the role of T1R1 or the gene it encodes Tas1r1, in sensing AAs in olfactory structures.

The brain is roughly 50% fatty acids (FAs) by weight making it the organ with the second highest lipid content after that of adipose tissue (Watkins et al., 2001). Cerebral lipids are uptaken from the blood or synthesized locally (Rapoport et al., 2001; Smith and Nagura, 2001). Indeed, brain neurons express enzymes for both intracellular metabolism and de novo synthesis of FAs (Le Foll et al., 2009). In the human brain, the main source of polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid, eicosapentaenoic acid, and arachidonic acid, is dietary. Even though free FAs are not the primary metabolic fuel for neurons, they are key components of membranes and intracellular signaling pathways. PUFAs are of great importance in neurobiology because they are essential for neurogenesis, memory, learning, and play a key role in modulating ion channels and neurotransmitter receptors. In fact, an adequate lipid environment is vital for the normal functioning of neuronal membrane proteins such as ion channels, enzymes, ion pumps, and receptors. Long-term nutritional PUFA deficiency impairs brain functioning (Khan and He, 2017). FA sensing in neurons was first reported by Oomura et al. (1975). Since then, a growing body of evidence has established the importance of brain FA sensing in the regulation of food intake (Loftus et al., 2000; Lam et al., 2005; Levin et al., 2011). Specific areas of the central nervous system including the hypothalamus, brainstem, and hippocampus (Gao and Lane, 2003; Lam et al., 2005; Picard et al., 2014) have been shown to use FAs as cellular messengers to inform “FA-sensitive neurons” about the energy status of the body (Migrenne et al., 2011). Similar to glucose sensing and AAs sensing described previously, lipid sensing is involved in the control of feeding behavior (Obici and Rossetti, 2003; Cruciani-Guglielmacci et al., 2004). Hypothalamic lipid sensing mechanisms are disrupted during conditions of prolonged fasting (Yue and Lam, 2012). The molecular mechanisms involved in FA sensing by the brain are still a matter of debate.

The FA transporter proteins (FATP also called SLC27), is a protein family of six isoforms. SLC27A4 (FATP4) is the major FATP expressed in the brain (Fitscher et al., 1998). In hypothalamic neurons, FAs are transported inside cells through FATPs. FAs are then oxidized to generate ATP that can modulate the activity of a wide variety of ATP-dependent ion channels including K⁺ channels, and the Na⁺-K⁺ ATPase pump. The resulting change in neuronal firing rate suggests that FAs metabolism play a role in the regulation of energy balance (Migrenne et al., 2011; Picard et al., 2014).

In the brain, membrane receptors mediating FAs sensing consist of two GPCRs (GPR40 and GPR120) and CD36, often associated to fatty acid translocase (FAT) to make a translocator/receptor complex FAT/CD36. CD36 has been reported to be involved in FA sensing in taste buds (Fukuwatari et al., 1997; Laugerette et al., 2005) and in hypothalamic neurons (Le Foll et al., 2009). Hypothalamic CD36 expression induced by fasting or following high-fat diet, could modulate lipid signaling in the brain and participate in the regulation of energy homeostasis (Moulle et al., 2012, 2014). All together, these findings strongly suggest that lipid sensing by CD36 is responsible for basic physiological functions in relation to behavior and energy balance (Martin et al., 2011). In the hypothalamus, it has been postulated that binding of FAs to CD36 alters neuronal activity in a manner analogous to that utilized for fat perception by taste receptor cells (Le Foll et al., 2009). This causes phosphorylation of protein tyrosine kinases, leading to generation of IP₃, recruitment of Ca²⁺ from the endoplasmic reticulum, followed by influx of calcium via opening of store-operated calcium channels, membrane depolarization via TRPM5 channel activation, and ultimately neurotransmitter release (El Yassimi et al., 2008).

In this review, only FA transporters (FATP/SLC27) and the FA receptors GPR40 and CD36 will be detailed. Intracellular proteins including long-chain fatty acyl-coenzyme A (CoA) synthetases and FA oxidative proteins are largely involved in neuronal FA sensing but are beyond the scope of this review (Picard et al., 2014).

In contrast to glucose and AAs sensing, only one study has explored the neuron lipid sensing in peripheral olfactory structures (Oberland et al., 2015). The fact that CD36, GPR40 and molecules involved in their intracellular pathways, are expressed in neurons of olfactory structures raises the question of their role(s) in lipid olfactory perception, central FA sensing, and regulation of energy balance. Indeed, lipid sensing is described as an important contributor to the regulation of energy balance (Magnan et al., 2015). In circumvallate taste buds, a decrease in CD36 expression induced by high-fat diet causes obesity and reduced sensitivity to fat taste, which in turn increased the intake of fatty foods as a compensatory response (Zhang et al., 2011). In the same way, reduction in hypothalamic CD36 expression induced redistribution of fat from visceral to subcutaneous deposits and markedly impaired insulin sensitivity (Le Foll et al., 2009, 2013, 2015). Growing evidence shows that dysregulation of brain FA sensing may contribute to energy imbalance and development of obesity, associated with type 2 diabetes or not (Yue and Lam, 2012; Picard et al., 2014). It will be interesting in future studies to investigate if olfactory dysfunction caused by altered energy balance (Thiebaud et al., 2014) could be linked to a change in expression of GPR40 and/or CD36.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.