Table 2.

Preclinical study characteristics and findings

Author (Reference), Year, Country	Sample Size	Animal Characteristics	Design/Methods	Key Findings
Ackroff and Sclafani (82), 2014, USA	N = 43 C57BL/6J (B6) Mus musculus (mice)	Age = 10 weeks old	Intralipid intragastric infusion	Intragastric (IG) administered self-infusions of fat produces concentration-dependent increases in the intake of and preference for a flavored solution in C57BL/6J mice. IG fat rapidly generates concentration dependent postoral signals that stimulate intake and enhance preferences for energy-dense foods.
		Sex = all male	Licking tests
		Groups = infusions of 1.6% (n = 11), 3.2% (n = 10), 6.4% (n = 11), or 12.8% (n = 11) intralipid	Two-bottle preference tests
Ahn et al. (83), 2017, USA	N = 22–124 Drosophila melanogaster (fruit fly)	Age = 3–7 days	Proboscis extension reflex (PER) assay	A novel role for IR25a and IR76b in fatty acid taste was established. These two subunits are not only critically important to elicit PER responses in flies when challenged with fatty acids but are also necessary for fatty acid induced Ca2+ increases in tarsal sweet gustatory receptor neurons (GRNs).
		Sex = all female flies	Immunofluorescence
		Groups = control, IR25a, and IR76b mutant	Calcium imaging
Ancel et al. (84), 2015, France	N = 10–12 C57Bl/6 mice	Age = young mice	Two-bottle preference tests	GPR120 disruption is not associated with fat preference or CD36 expression in circumvallate papillae. However, GPR120 agonist, grifolic acid, triggered a rise in [Ca2+]i which was drastically decreased when GPR120 was disrupted. These data suggest that although GPR120 is expressed in lingual tissue, it is not required for oral fat detection.
		Sex = all male	Licking tests
		Groups = wild type (WT) and GPR120−/−	Conditioned taste aversion tests
			Measurement of Ca2+-signaling in taste bud cells (TBC)s
Avalos et al. (85), 2020, USA	N = 5–8 (per group) C57BL/6Tac male mice and CB1R-deficient mice	Age = 8–10 weeks	Western diet preference test	Preference for the Western high-fat diet (HFD) was significantly decreased after pharmacological blockade of CB1R. HFD preference was also decreased for CB1R−/− mice, showing that CB1 in the intestinal epithelium plays a role in fat preference.
		Sex = all male	Pharmacological blockade of cannabinoid receptor type 1 (CB1R)
		Groups = WT and CB1R−/−	Utilizing CB1R−/− mice
Avau et al. (86), 2015, Belgium	N = 32 C57BL/6J mice	Age = adult mice	Comparing WT with knockout mice on HFD	α-Gustducin knockout mice did not gain as much weight as WT mice on HFD. Intragastric administration of bitter agonists caused further weight loss via α-gustducin pathway. Therefore, α-gustducin is involved in induction of obesity during HFD.
		Sex = not specified	Comparing food intake after administration of bitter tastants vs. control
		Groups = WT and α-gustducin−/−	Respiratory quotient/heat production measurements
Bensalem et al. (87), 2020, France	N = 24 C57B1/6 mice	Age = 12- to 14-week-old mice	Comparing WT with knockout mice on standard/HFD	The TGR5−/− obese mice exhibited high daily food/energy intake, fat mass and inflammatory status. TGR5−/− obese mice maintained an attraction for lipids. In TBCs, the fatty acid-triggered Ca2+ signaling was increased in TBC from TGR5−/− obese mice. TGR5 may modulate fat eating behavior and obesity.
			Analysis of lean/fat mass
		Sex = all male mice	Two-bottle preference test
			LPS assay
		Groups = WT and TRG−/−; standard chow and high-fat-chow mice	Taste bud isolation from CV
			Measurement Ca2+ signaling
Boone et al. (88), 2021, USA	N = 5–22 (per group) C57BL/6J mice	Age = >8 weeks	Olfactory bulb ablation and anosmia screening	Anosmic mice (following complete removal of the olfactory bulb) and sham mice (with intact olfactory bulbs) both displayed comparable HFD intake. HFD smell (in the absence of consumption) did not alter feeding or devaluation of standard food. Thus, while the olfactory bulb may play a role in fat-olfaction it may not be necessary for the development a HFD preferential consumption.
		Sex = both: male and female	Inaccessible and short accessibility food experiments
		Groups = standard diet (SD), SD + HFD, and SD + inaccessible HFD	Fast-refeed tests
			Measuring SD and HFD consumption of control and anosmic mice
Braymer et al. (89), 2017, USA	N = 5–9 (per group) obesity-prone (OP) and obesity-resistant (OR) S5B/P1 rats	Age = 8–9 weeks old	Linoleic acid (LA) preference testing	Lingual CD36 mRNA levels increased in OR rats, but not in OP rats. Lingual application of CD36 siRNA decreased LA preference in OR rats, but not in OP rats. OP rats did not show other effects of CD36 siRNA on HFD preference or HFD or LFD intake.
		Sex = all male	Administration of lingual CD36 siRNA
		Experiment 1: effect of fasting- 16-h fast (OP n = 8; OR n = 7) + standard chow (OP n = 8; OR n = 8)	Effect of fasting: 16-h fast + chow
		Experiment 2: effect of HFD on LA preference (OP n = 5; OR n = 5)	Effect of HFD: HFD vs. chow fed
		Experiment 3: effect of fasting lingual CD36 mRNA expression + standard chow (OP n = 6; OR n = 6), fasted overnight (OP n = 9; OR n = 6), refed for 2 h (OP n = 7, OP n = 7)
Brown et al. (90), 2021, USA	N = 13–41 (per trial) IR56d Drosophila melanogaster	Age = 7–9 days	Aversive taste memory	Flies were able to discriminate medium-chain fatty acids (MCFAs) from short-chain fatty acids (SCFAs) and long-chain fatty acids (LCFAs). They were not able to discriminate different MCFAs from each other. Similar discrimination abilities were exhibited in both males and females.
		Sex = all female
Buttigieg et al. (91), 2014, Chile	N = 5–12 (per group) Swiss CD1 mice	Age = weaned mice	RD vs. HFD chow preference tests	After 18 days (short term) exposure to HFD, mice developed preference for high fat chow, indicating that high fat preference is not spontaneous in CD1 mice, but can be acquired after short term exposure to HFD. Development of preference for HFD dependent on NMDA receptor signaling.
		Sex = all male	HF preference tests after 18-day exposure to either RD or HFD
		Groups = Exp1 group (n = 12); Exp2: regular diet (n = 9) and high-fat diet (n = 9); Exp3: IP injections of ketamine, ifenprodilMK-801, or PBS (control), (n = 5 per group)	NMDA antagonist injections during HFD with preference tests
Calder et al. (92), 2021, USA	N = 66 C57BL/6J WT and Growth Hormone Secretagogue Receptor knockout (Ghsr -/-) mice	Age = 6 weeks old	Conditioned taste aversion assay	GHSR expression within the taste system- with GHSR being largely present in type II cells. Additionally, HFD-fed female GHSR-/- exhibited reduced responsiveness to LA (compared to WT). Ghrelin signaling may play a critical role in the recognition of fatty acids in female mice, and this may contribute to ingestive behaviors.
		Sex = both: female (n = 33) and male (n = 34)
		Groups = WT (n = 37) and Ghsr-/- (n = 29)
Camandola and Mattson (93), 2017, USA	N = 5–19 mice per group	Age = adult mice	Two-bottle preference test	TLR4 knockout mice show low preference for fat. TRPM5 and G-protein dependent phospholipase Cb2 significantly decreased in TLR4 knockout. Overall, TLR4 promotes fat ingestion (FA endocytosis) and preference for fat intake.
		Sex = all male	Comparing standard diet and obese diet
		Groups =WT and TLR4 knockout mice; standard diet and high-fat, high-sugar diet	Tongue epithelium PCR
De la Cruz et al. (94), 2015, USA	N = 37 Sprague-Dawley rats (260−300 g)	Weight = 260- to 300-g rats	Feed rats test solutions	Corn oil caused dopaminergic signaling, measured by c-Fos-like immunoreactivity, in the ventral tegmental area, infralimbic/prelimbic prefrontal cortex, dorsal striatum, nucleus accumbens core, and basolateral/central-cortico-medial amygdala. This suggests that these brain regions may form a distributed network to help mediate fat intake.
		Sex = all male	Brain tissue collection	Consumption of corn oil solutions, isocaloric to glucose and fructose, significantly increased FLI in all sites except for the NAc shell.
		Groups = water (n = 7), cherry-flavored saccharin (0.2%) (n = 7), corn oil in xanthan gum (3.5%) (n = 5), fructose (8%) (n = 7), glucose (8%) (n = 7), and saccharin, xanthan gum (0.3%) (n = 4)	Immunoreactive c-Fos quantification
Devineni et al. (95), 2019, USA	N = 6–18 (per trial group/set) Drosophila melanogaster	Age = 3–6 days old	PER experiments were conducted by taste stimulation of the labellum	Fed flies show taste aversion to acetic acid, whereas starved flies show a robust appetitive response. These opposing responses are mediated by two different classes of taste neurons, the sugar- and bitter-sensing neurons.
		Sex = mated all females	Taste stimuli
		Groups = Gr64f-Gal4; Gr66a-Gal4; ppk28-Gal4; Gr98d-Gal4, Gr22f-Gal4, Gr59c-Gal4, and Gr47a-Gal4; UAS-Kir2.1; UAS-GCaMP6f, UAS-norpARNAi,, poxnΔM22-B5 and poxn ΔM22-B5+ SuperA rescue; Δ8Grs (R1, ΔGr5a; ΔGr61a, ΔGr64a-f) and Δ8Grs with transgenes for GCaMP imaging (R1, ΔGr5a; Gr61a-Gal4, UAS-GCaMP6m; ΔGr61a, ΔGr64a-f); IR25a1 and IR25a2; IR76b1 and IR76b2	Surgery was performed prior to starvation, and after surgery flies were given∼30 min to recover in food vials before starvation
			Calcium imaging
Djeziri et al. (96), 2018, France	N = 6 (per group) C57B1/6J mice	Age = 6–10 weeks	Two-bottle preference test	HFD mice showed decreased CD36 expression. OLA-treated obese mice showed increased CD36 mRNA in TBC. They exhibited higher preference for fat and more sensitive orosensory detection of OLA. Oleic acid triggered an increase in intracellular calcium in mTBCs. Oleic acid-induced increases in Ca2+ were abolished completely in the presence of SSO, a selective CD36 inhibitor.
		Sex = all female	Two-bottle preference test
		Groups: WT (n = 6), HFD (n = 6), HFD + OLA (n = 6)	Blood glucose tolerance test
			Plasma LPS, insulin, liver lipids analyses
			Fatty acid analysis
			Measurement of Ca2+ signaling
			Isolation of mTBCs
Espitia-Bautista and Escobar (97), 2019, Mexico	N = 80 (10 per group) Wistar rats	Age = not specified	Assessment of binge-type eating, food anticipatory activity, and effort behavior to obtain the diet.	After an acute exposition, rats ate more SRD than FRD, but FDR stimulated higher c-Fos. After chronic administration, the FDR group exhibited higher levels of BTE and FAA; this was associated with higher c-Fos and accumulation of ΔFosB in the corticolimbic system.
		Sex = all male	Immunohistochemistry
		Groups = (n = 10)
		Experiment 1: sugar-rich diet (SRD) and fat-rich diet (FRD) 8 groups: SRD = 10%, 25%, 50%, 75% FRD = 10% 25%, 50%, 75%
		Experiment 2: 3 groups: chow; 50% SRD, 50% FRD rats
		Experiment 3: groups: chow, Daily 1 h restricted access to 50% SRD, or to 50% FRD
		Experiment 4: 3 groups: chow; 50% SRD; 50% FRD
Fardone et al. (98), 2019, USA	N = 72 M72-IRES-tauGFP mice with mixed agouti/C57BL6/J	Age = not specified	Odor (Olfr160 ligand) exposure	Neuronal excitability of juxtaglomerular (JG) cells is significantly reduced in moderate HFD (MHF) and HFD mice when stimulated by a preferred odorant, whereas control animals showed normal activation. This is mainly seen in interneurons surrounding the lateral but not medial glomerulus. Diet-induced obesity (DIO) causes deleterious effects on OSN survival that extends to a reduced neuronal activity of JG cells surrounding the genetically identified glomerulus for that class of ORs.
		Sex = all male	c-Fos immediate-early gene expression for neuronal activity mapping
		Groups = control food (n = 24), moderately high-fat diet (n = 19), high-fat diet (n = 29)	IPGTT
Gaudet et al. (99), 2019, USA	N = 39 Sprague-Dawley rats	Age = 8–10 weeks	Comparing expression levels of taste-related genes between standard chow diet vs. continuous, daily, and intermittent HFD access	Expression levels of the fat taste-sensing markers, CD36, SERT, and TPH2 mRNA in the circumvallate papillae were higher in the continuous HFD group.
		Sex = all male
		Groups = chow diet (n = 14), continuous HFD (n = 9), daily (n = 8), intermittent (n = 8)
Olvera Hernández et al. (100), 2021, France	N = 48 Wistar rats	Age = 3 months	Evaluation of preferences for fatty and sugary foods	Adult males and females born to undernourished dams exhibited increased expression of Cd36, Trpm5, Plc-b2 in the hypothalamus. The severity was greater in females. Only males from undernourished dams consumed more standard and sweetened food and had higher AgRP NPY in hypothalamus and increased dopamine transporter and dopamine receptor d2 in VTA.
		Sex = both: female (n = 24) and male (n = 24)	Tissue collection from the tongue, nucleus accumbens, and ventral tegmental area (VTA) in the brain
Iskhakov et al. (101), 2019, USA	N = 30 inbred BALB/c, C57BL/6 and SWR mice	Age = 6 weeks	Scopolamine injections and comparing intralipid intake	Scopolamine (muscarinic receptor antagonist) reduced fat intake in all 3 strains and eliminated the ability to learn fat-CFP in the 3 strains. Therefore, muscarinic receptor signaling mediates learning and to a lesser degree maintenance of fat-CFP while maximally inhibiting fat intake in the 3 strains.
		Sex = all male	Fat-conditioned flavor preference (CFP) tests
		Groups = (n = 10 per group) BALB/c, C57BL/6, and SWR
Jung et al. (102), 2018, Korea	N = 20 Canton-S wild-type Drosophila melanogaster	Age = adult flies	Life span assays	A HFD reduced DmOrco gene expression by 70% in olfactory neurons and decreased olfactory sensitivity to short-chain fatty-acids. This suggests HFD leads to olfactory dysfunction in homeostatic processing in Drosophila.
		Sex = all male	Climbing assays
		Groups = (n = 20 per vial on HFD and SD)	Odor stimulation
			Behavioral assay
			Electrophysiological readings
Khan et al. (103), 2017, France	N = 7 per group C57BL/6J WT and Erk1-/- mice	Age = <9 weeks	Comparing standard diet vs. HFD	Erk1-/- exhibited a low preference for dietary fatty acids and developed obesity. They also showed higher phosphorylation of MEK, an upstream regulator of ERK1/2 and exhibited high ERK2 phosphorylation, high lipogenesis, and low fatty acid oxidation. Overall, ERK1 and ERK2 have different but key roles in obesity.
		Sex = all male	OGTT
		Groups = (n = 7 per group) WT-normal diet (ND), Erk1-/- ND, WT-HFD, Erk1-/- HFD	Lipid analysis
			Western blots
			mRNA RT-qPCR
Kim et al. (104), 2018, Korea	N = 3–25 Drosophila melanogaster per trial group	Age = 3–5 days old	CRISPR/Cas9 Gr64 cluster deletion	Gr64e, a gustatory receptor, is required for the behavioral and electrophysiological responses to fatty acid detection. It functions as an ion-gated ligand channel for glycerol detection and acts downstream of phospholipase C signaling.
		Sex = both: mated males and females	Proboscis extension reflex assay
		Groups = multiple Gr64e mutant groups
Kraft et al. (105), 2017, USA	N = 35 BALB/c and SWR mice	Age = 6 weeks old	Two-bottle conditioned stimuli (CS) choice test	Preference response for flavor associated with higher intralipid content was eliminated in mice treated with 100ug/kg MK-801. Therefore, NMDA receptor signaling must be needed in the formation of major triggers toward fat preference learning.
		Sex = all male	Systemic NMDA antagonist (MK-801) injections
		Groups = vehicle control (BALB/c, n = 8; SWR, n = 9) and MK-801 (BALB/c, n = 9; SWR, n = 9)
Lacroix et al. (106), 2015, France	N = 19 OR and OP Sprague-Dawley rats	Age = 4 weeks old	Weight recorded	In OP rats, 1) decreased odor threshold, but 2) poor olfactory performances, associated with learning/memory deficits, 3) decreased influence of fasting, and 4) impaired insulin control on food-seeking behavior were reported. Modulation of metabolism-related factors implicated in 1) electrical olfactory signal regulation (insulin receptor), 2) cellular dynamics (glucocorticoids receptors, pro- and antiapoptotic factors), and 3) homeostasis of the olfactory mucosa and bulb (monocarboxylate and glucose transporters).
			Food intakes were recorded during the diurnal and nocturnal phases of the day
			Insulin tolerance test
		Sex = all male	Concentrations of glucose, triglycerides, insulin, and leptin were measured
			Tea-ball (odor) test
			Conditioned odor aversion test
		Groups = OR (n = 9) and OP (n = 10)	Hidden cookie test
			Western blot analysis
			Quantitative real-time RT-PCR
Lee et al. (107), 2015, Japan	N = (not specified) C57BL6/J WT and CD36-knockout mice	Age = 8–12 weeks old	Two-bottle choice test	WT mice avoided solutions with KOdiA-PC (CD36 ligand), an irritant phospholipid species CD36. Knockout effects are only seen at low levels of KOdiA-PC, suggesting that CD36 contributes to lipid recognition, but may not be the sole receptor. Mice that had olfactory nerve transected could not perceive KOdiA-PC. This implies that CD36 may operate in a nasal capacity and contribute to olfactory lipid detection.
		Sex = not specified	Licking test
		Groups = control, CD36 knockout; surgical control, olfactory nerve transected	Olfactory nerve transection
Lee et al. (108), 2017, Japan	N = 18 C57BL/6J and CD36 knockout mice	Age = 8–12 weeks	Two-bottle choice test	WT mice discriminated a sucrose solution with oleic aldehyde from sucrose solution alone in the two-bottle choice test. CD36 knockout mice did not discriminate the differences in solutions and fed on both bottles equally. WT mice also exhibited increased exploratory behavior (including sniffing) for an oleic aldehyde vehicle compared to the control, while CD36 knockout mice did not. These behavioral tests display the role of CD36 in fat taste and olfaction.
		Sex = all female	Exploration test to assess sniffing behavior
		Groups = WT (n = 8) and CD36 knockout (n = 10)
Liu et al. (109), 2021, USA	N = 5–10 mice for nerve analysis, 16 mice for CTA assays	Age = 2–6 months	Calcium imaging	GPR84 mRNA expression was found in mouse fungiform and CV papillae. MCFAs were found to activate mouse TBCs via increases in intracellular calcium concentration. Gpr84−/− mice also exhibited significantly reduced taste nerve response to MCFAs and reduced taste responsiveness in the controlled taste aversion assay compared to WT. GPR84 is therefore implicated in the detection of MCFAs.
		Sex = all male	CT nerve recording
		Groups = WT and Gpr84−/−	Conditioned taste aversion assay
Makarova et al. (110), 2021, Russia	N = 37 C57Bl/6J diet-induced obese mice 24 mice in experimental groups	Age = 12–26 weeks	Administration of HFD to induce obesity	In females, they found that FGF21 administration reduced the preference for fatty food. However, food intake was not significantly different.
		Sex = both: females (n = 10) and males (n = 14)	Injection of PBS control or FGF21
		Groups = control PBS (n = 12) and FGF21 (n = 12)	Real-time PCR
Mathes et al. (111), 2015, USA	N = 40 (2 groups of 20) Sprague-Dawley rats	Age = 2 weeks apart. First set: 2 months and second set: 1.5 months of age	Progressive ratio (PR) behavioral task	When tested before surgery while nondeprived, HFD rats had lower PR breakpoints (number of operant responses in the last reinforced ratio) for sucrose, but not for Ensure, than CHOW rats. After surgery, at no time did rats given RYGB show lower breakpoints than SHAM rats for Ensure, sucrose, or when 5% Intralipid served postoperatively as the reinforcer.
			Surgery and recovery procedure
		Sex = all male	Two-bottle preference test
			Food-deprived testing
		Groups = chow group (average body weight = 262 g) and HFD group (average initial body weight = 225 g)	Kruskal-Wallis tests
			Friedman tests
Murtaza et al. (112), 2017, France	N = 20 C57B1/6J mice	Age = 12 weeks	Zizyphin extraction and purification	Preference for LA solution was significantly increased when zizyphin was added to a LA solution (compared to LA alone), suggesting it is involved in modulating fatty acid perception. Zizyphin trigger opening of Ca2+ channels in hTBC. Zizyphin does not act on fatty acid receptors.
		Sex = all male	Measurement of calcium signaling in human taste bud cells (hTBCs)
		Groups: WT (n = 10), Gpbar1 -/- (n = 10)	Two-bottle preference test
Murtaza et al. (113), 2020, France	N = not specified wild-type C57BL/6J mice	Age = 2 months old	Isolation and culture of mTBCs	In cultured mouse and human TBCs, TUG891 induced a rapid increase in Ca2+ by acting on GPR120. LA, also recruited Ca2+ via GPR120 in human and mouse TBCs. Both TUG891 and LA induced ERK1/2 phosphorylation and enhanced in vitro release of glucagon-like peptide-1 from cultured human and mouse TBCs. Mice exhibited a spontaneous preference for solutions containing either TUG891 or LA instead of a control. However, addition of TUG891 to a solution containing LA significantly curtailed fatty acid preference.
		Sex = all male	Ca2+ signaling measurement
		Groups = one group received the test solution and the other a control solution	Western blot analysis
			GLP-1 measurement
			ELISA
			Licking test
			Two-bottle test
Murtaza et al. (114), 2021, France	N = 3–5 mice/condition	Age = 2 months	Measuring of Ca2+ signaling in TBC	TRPC3 was found to play a role in the orosensory detection of dietary lipids. Inactivation of TRPC3 in mTBCs caused a decreased in fatty acid induced Ca2+ signaling. Preference for a dietary LCFA was also abolished in TRPC3 KO mice. The same effect was seen in mice where TRPC3 was blocked via lingual application of an siRNA.
		Sex = all male	Two-bottle preference test
		Groups = WT C57BL/6J and TRPC3−/−	TRPC3 knockdown by siRNA
Ozdener et al. (115), 2014, USA	N = 20–40 cells per experiment/run human and C57BL/6J mice taste bud cells (TBCs)	Age = not applicable (isolated cells)	siRNA transfection	High concentrations of LA induced Ca2+ signaling via CD36 and GPR120 in human and mice TBC; low concentrations induced Ca2+ signaling via only CD36. Incubation of human and mice fungiform TBC with linoleic down-regulated CD36 and up-regulated GPR120 in membrane lipid rafts. Fungiform TBC from obese mice had reduced levels of CD36 and increased levels of GPR120 in lipid rafts. Therefore, CD36 is necessary for fat detection, while GPR120 only amplifies response of high concentrations of LA, acting downstream of long-chain fatty acid receptors.
		Sex = not specified	Isolation of CD36−/−
		Groups = CD36 and GPR120 siRNA-transfected human TBC, LA-human TBC, Grifolic acid-human TBC, CD36-/-, WT lean and WT obese TBC	Measurement of Ca2+ signaling in TBC
			Serotonin and GLP1 secretion measurement
Peterschmitt et al. (116), 2018, France	N = 6 mice per group	Age = 6–10 weeks old	Addition of LA to circumvallate papillae	LA induced a significant increase in c-Fos expression in the nucleus of the solitary tract (NTS), parabrachial nucleus (PBN), and ventroposterior medialis parvocellularis (VPMPC) of the thalamus, which are the regions known to be activated by gustatory signals. LA also triggered c-Fos expression in the central amygdala and VTA, involved in food reward, in conjunction with emotional traits.
		Sex = all male	Immunocytochemical localization of c-Fos
		Groups = lingual application of LA group vs. no application	mRNA expression of BDNF, Sif-268, and Glut-1
Ricci et al. (117), 2018, Italy	N = 7–10 (per group) C57BL/6J Prep1i/+ mice	Age = 6 months	Macromorphological analysis of brain structural alterations	Prep1 deficiency alters olfactory morpho-functional integrity and olfaction-mediated eating behavior by affecting BDNF-TrkB signaling. Prep1 could play an important role in behavioral dysfunction associated with responsiveness to BNDF.
		Sex = all male	Hemalum and COX Staining
		Groups = macromorphological analysis and COX staining- C57BL/6J (n = 7) Prep1i/+ (n = 7) for behavioral-C57BL/6J (n = 9) and Prep1i/+ (n = 9)	Immunofluorescence
			Behavioral (open field, olfactory preference, food preference)
			Western blotting
			Real-time (RT-PCR)
			Cell viability assay
Sakamoto et al. (118), 2015, Japan	N = 8–12 (per group) BALB/c mice	Age = 8 weeks old	Two-bottle choice test	The opioid system seems to have a greater role in determining the palatability of high-fat foods unlike the contribution of olfactory and glossopharyngeal nerves.
		Sex = all male	Olfactory nerve transection (ONX)
		Groups = water vs. intralipid (n = 12), water vs. intralipid +/- naltrexone (0.5 or 2 mg/kg, n = 8 Sham vs. ONX (n = 8) Sham vs. GLX (n = 8) ONX and GLX +/- naltrexone (n = 12)	Glossopharyngeal nerve transection (GLX)
			Operant lever-press paradigm: progressive (PR) schedule
Sakamoto et al. (119), 2015, Japan	N = 7–10 (per group) BALB/c mice	Age = 8 week old	Two-bottle choice test	In mice, preference of fat relies strongly on the opioid system, while that of sucrose is regulated by other mechanisms in addition to the opioid system.
			Preference between sucrose and intralipids in naive mice + opioid receptor antagonists
		Sex = all male	Preference between sucrose and intralipids following naltrexone
			Preference between sucrose and intralipids following food deprivation in naive mice
		Groups = saline, naloxanazine, naltrindole, Nor-BNI (n = 8) saline vs. naltrexone (n = 8) food deprivation (n = 7) Saline vs. naltrexone compared to water in naïve (n = 8) Saline vs. naltrexone in licking behavior (n = 10)	Preference between sucrose and intralipids compared to water in naive mice
			Licking behavior for sucrose and intralipids in naive mice
Sasaki et al. (120), 2017, Japan	N = 3–10 (per group) C57BL/6J	Age = 8–10 weeks old; except for in CTA experiment mice were 12–14 weeks	d-serine IP injection effect on HFD consumption	IP-injected d-serine inhibited HFD intake and acquisition of an HFD preference. Individual mice with the same genetic background showed different sensitivities to d-serine; thus d-serine sensitivity may be associated with unidentified traits.
		Sex = all male	d-serine IP injection effect on CTA
		Groups = HFD vs. NC + saline or IP d-serine day 0 (n = 6), day 1 (n = 7), day 2 (n = 8), and day 4 (n = 7) IP d-serine (n = 9) vs. LiCl (n = 8) brain d-serine (n = 3), and L-serine (n = 3) post-IP D-serine IP D-serine vs. VEH (n = 6/group) IP D-serine + water or lipid emulsion (n = 6/group)	d-serine and l-serine levels pre- and post-IP d-serine
			Single IP d-serine injection effect on HFD preference effect of intraperitoneally injected d-serine under the single-food access paradigm using liquid meals (water or lipid emulsion)
Schreiber et al. (121), 2020, USA	N = 4–10 (per group) OP and OR S5B/PI rats	Age = 8–9 weeks old	Transection of glossopharyngeal nerves	OR rats had a higher fungiform papillae density than OP rats. Transection of glossopharyngeal nerves decreased HFD intake in OR rats and had no change in OP rats.
		Sex = all male	Comparing the effect of GLX/CTX on quinine intake
		Groups = fungiform papillae assessment: OP (n = 6), OR (n = 5)	Comparing the effect of GLX/CTX on HFD and LFD intake
		Effect of GLX/CTX on quinine intake: OR-Sham (n = 5), OR-GLX/CTX (n = 5), OP-Sham (n = 4), OP-GLX/CTX (n = 4)
		Effect of GLX/CTX on HFD and LFD intake: OR-SHAM-LFD (n = 10), OR-GLX/CTX-LFD (n = 8), OR-SHAM-HFD (n = 11), OR-GLX/CTX-HFD (n = 10), OP-SHAM-LFD (n = 11), OP-GLX/CTX-LFD (n = 8), OP-SHAM-HFD (N = 10), OP-GLX/CTX-HFD (n = 9)
Sclafani and Ackroff (122), 2014, USA	N = 11 (per group) P2X2/P2X3 double knockout mice (P2X DoKO)	Age = 11–14 weeks old	Utilize P2X DoKO to examine maltodextrin preference for polycose solutions (vs. water)	Preference of mice for maltodextrin and fat are dependent on adenosine triphosphate taste cell signaling. With experience, however, P2X DoKO mice develop strong preferences for the nontaste flavor qualities of maltodextrin and fat conditioned by postoral actions of these nutrients.
		Sex = all male	Utilizes P2X DoKO to examine fat preference to intralipid (vs. water)
		Group = P2X DoKO (n = 11), WT (n = 11)
Sclafani et al. (123), 2015, USA	N = 12 per group GPR40/120 double knockout and C57BL/6J wild-type mice	Age = 15 weeks old	Utilizes DoKO GPR40/120 to examine if GPR40 and GPR120 play a role in intralipid and glucose preference	Postoral GPR40/120 signaling is not required to process IG fat infusions in food-baited spout training sessions but contributes to postoral fat reinforcement in empty spout tests and flavor conditioning tests.
		Sex = all male
		Group = GPR40/120 double knock out (n = 12), C57BL/6J WT (n = 12)
Sclafani et al. (123), 2015, USA	N = WT C57BL/6J and GHSR null mice	Age = adult-age not specified	Utilizes GHSR-null mice	Ghrelin receptor signaling is not required for flavor preferences conditioned by the oral or postoral action of sugar and fat.
		Sex = both:
		Exp1: 9 females, 10 males	Flavor conditioning
		Exp2: male
		Exp3: 9 female, 13 males	Intragastric feeding
		Exp4–9: female, 13 males
		Exp5–11: female, 11 males
		Exp6–12: female, 12 males
		Groups:
		Exp1: GHRS-null vs. WT+/− CS+/CS-
		Exp2: CS+/glucose, CS+ S + S, CS-/S + S
		Exp3: GHRS-null mice vs. WT+ CS+/CS- +GHSR antagonist
		Exp4: GHRS-null mice vs. WT+ CS+/CS- +IG intralipid/IG water
		Exp5: food-deprived GHRS-null mice vs. WT+ CS+/CS- +IG intralipid/IG water Exp6- GHRS-null mice vs. WT
Sclafani and Ackroff (124), 2018, USA	N = CAST/EiJ (n = 10) and C57BL/6J mice (n = 10)	Age = 9 weeks old	Compare the preferences of CAST and B6 mice for fat vs. sugar and maltodextrin vs. water in 2-day choice tests	CAST/EiJ mice strongly prefer fat to isocaloric carbohydrate (sucrose, maltodextrin). C57BL/6 J mice show the opposite preference profile. CAST/EiJ mice show weaker fat preferences in fat vs. water tests compared to C57BL/6 J. CAST/EiJ mice, like C57BL/6 J mice strongly prefer sweetened fat to maltodextrin. Taste rather than postoral factors is implicated in the low-fat preferences of CAST/EiJ mice.
		Sex = all male
		Groups = CAST & B6
Sclafani and Ackroff (125), 2018, USA	N = not specified CD36 KO mice	Age = 11 weeks	Use of CALHM1 knockout (KO) to evaluate the primary role of CD36 as a taste receptor mediating fat preference	Naïve CD36 KO mice displayed reduced preferences for soybean oil emulsions (intralipid) at low concentrations (0.1–1%). CALHM1 KO mice displayed even greater Intralipid preference deficits compared with WT and CD36 KO mice. This suggests there may be other taste receptors other than CD36 (but also through CALHM1). After experience with concentrated fat (2.5–5%), CD36 KO and CALHM1 KO mice displayed normal preferences for 0.1–5% fat, the experience-induced rescue of fat preferences in KO mice can be attributed to postoral fat conditioning.
		Sex = all male
		Groups = CAST & B6
Subramaniam et al. (126), 2016, France	N = 164 C57B1/6J mice, X Erk-1-/- C57B1/6J mice, X calhm1-/- C57B1/6J mice	Age = 22.2 ± 1.8	Measurement of calcium signaling	Fat preference is decreased by downregulation of ERK1/2. LA induces MAPK activation in hTBCs. Src-kinases and raft integrity are involved in LA-induced ERK1/2 activation in hTBCs. LA induces ERK1/2 phosphorylation via CD36 in hTBCs. CALHM1 channels are upstream regulators of LA-induced ERK1/2 phosphorylation. LA-induced Ca2+ signaling and ERK1/2 phosphorylation are impaired in Calhm1−/− TBCs. Preference for fat is abolished in Calhm1−/− mice.
		Sex = both: male (n = 2), female (n = 17)	Lipid raft isolation
		Groups = orosensory detection of LA	Licking and 2-bottle preference tests
Tauber et al. (127), 2017, USA	N = 9–49 Drosophila flies per experiment	Age = 7–9 days old	Measured proboscis extension reflex	Neurons expressing IR56d are necessary and sufficient for reflexive feeding response to FAs in Drosophila. IR56d/Gr64f neurons are activated by medium-chain FAs and are sufficient for reflexive feeding response to FAs. Flies can discriminate between sugar and FAs in an aversive taste memory assay, indicating that FA taste is a unique modality in Drosophila.
		Sex = all female	Uses Ca2+ sensor GCAMPS under control of, e.g., Gr64g-GAL4, IR56d-GAL4, etc.
		Groups = not specified	Selective silencing and expression
			Examination of neuronal activity
Tsuzuki et al. (128), 2016, Japan	N = not specified	Sex = not specified	oxLDL-CD36 binding/inhibition assays	Z,Z-TTD is an odor-active fatty aldehyde that is recognized by CD36 in the (nose). Aldehyde functional groups on fatty acid chains are especially important for CD36 lipid recognition. This suggests that CD36 in the mucus layer of olfactory tissue binds to specific lipids and relays them to olfactory receptors.
		Groups = control and CD36 peptide residues	Fluorescence measurement
Weiss et al. (129), 2019, USA	N = 78 male Sprague-Dawley rats	Age = 8 weeks	Body composition monitoring	A high-energy diet produces blunted, but more prevalent, responses in the nucleus of the solitary tract (NTS), and weaker association of taste responses with ingestive behavior.
		Sex = all male	Taste stimuli and odor stimuli testing
		Groups = diet-induced obese (n = 39 ); lean (n = 39)	Electrophysiology testing in operant chamber
Wu et al. (130), 2017, Korea	N = xC57BL/6J WT, ob/ob, and Olf544−/− mice	Age = 8 weeks old	Microarray + qPCR of olfactory receptors in liver and adipose tissue	Azelaic acid (a FA) is a ligand of Olfactory receptor 544 (Olfr544). Olfr544 orchestrates the metabolic interplay between the liver and adipose tissue, mobilizing stored fats from adipose tissue and shifting the fuel preference to fats in the liver and BAT.
			CRISPR/Cas9 to generate Olfr544-/-
		Sex = all male	Administration of 60% HFD + 50 mg/kg of Olfr544 agonist AzA
			OGTT + ITT
		Groups = HFD + azelaic acid (AzA), Olf544−/−, and ob/ob	Micro-CT for adipocyte tissue measures
			Histological analysis of BAT
			Quantification of hepatic triglycerides
			Indirect calorimetry
Xavier et al. (131), 2016, Brazil	N = 6 Cd36obl/Mmucd mice, n = 6 Olfr17tm7Mom MomJ mice, and n = 4 C57BL/6JB WT mice	Age = 4 weeks old	RT-PCR for Cd36 transcripts in olfactory epithelium	The Cd36 receptor is highly expressed in a small subset of mature olfactory sensory neurons in the main olfactory epithelium. In addition, the main olfactory epithelium expresses distinct populations of sensory neurons, typically dependent on the receptor they express. Cd36-deficient mice show normal general olfactory behaviors but do not show a preference for a lipid-odor mixture compared to WT mice.
		Sex = all male	In situ hybridization and immunofluorescence staining to determine which cells Cd36 is present in
		Groups = Cd36obl/Mmucd and wild-type C57BL/6J and Olfr17tm7Mom/MomJ (P2-IRES-tauGFP) mice	Behavioral assays to study olfactory behavior upon lipid exposure
Yasumatsu et al. (132), 2018, Japan	N = 7–9 C57BL/6JB WT and GPR120-KO mice per group	Age = 8–20 weeks	Single-fiber nerve response recordings from CT nerve	Pharmaceutical blockade of GPR120 caused suppression of CT nerve responses to fatty acids in WT mice. GPR120-KO mice also exhibited a higher threshold for LA detection than WT mice.
		Sex = all male	CTA experiments on WT and GPR120-KO mice
		Groups = WT and GPR120-KO	Chemical stimulation of the tongue with GPR120 antagonist

WT, wild type; HFD, high-fat diet; CS, conditioned stimuli; OLA, oleic acid; TBC/LPS, taste bud cells/mouse tas; lipopolysaccharide; CV, circumvallate; LA, linoleic acid; IP, intraperitoneal; CFP, conditioned flavor preference; RD, regular diet; NMDA, N-Methyl-d-aspartate; RT-qPCR, quantitative polymerase chain reaction/reverse transcription polymerase chain reaction; PER, proboscis extension reflex; IPGTT, intraperitoneal glucose tolerance test; OGTT, oral glucose tolerance test; CRISPR, clustered regularly interspaced short palindromic repeats; CS, conditioned stimulus; GLP-1, glucagon-like peptide 1; ELISA, enzyme-linked immunosorbent assay; FGF21, fibroblast growth factor 21; BDNF, brain-derived neurotrophic factor; OP, obesity prone; OR, obesity resistant; COX, cytochrome c oxidase; OSNs, olfactory sensory neurons; ONX, olfactory nerve transection; GLX, glossopharyngeal nerve transection; GHSR, growth hormone secretagogue receptor; OGTT, oral glucose tolerance test; ITT, insulin tolerance test; CT, computed tomography; BAT, Bayesian analysis toolkit; TRPC, transient receptor potential canonical; CD36, cluster of differentiation 36.