Oral fatty acid signaling and intestinal lipid processing: Support and supposition
Highlights
► Free fatty acids are effective signaling molecules in the oral cavity of humans though there is marked inter-individual variability in sensitivity. They are ligands for an array of putative fat receptors on taste receptor cells, but may also activate olfactory and trigeminal neurons. ► Oral fat detection influences lipid metabolism. It promotes a rapid rise in serum triacylglycerol, possibly by mobilizing lipid stored in the enterocyte from the previous eating event as well as by reducing the clearance rate through reduced adipocyte lipoprotein lipase activity. ► Oral (taste) detection thresholds for free fatty acids are not related to BMI, but there is a positive association between BMI and the post-stimulation serum triacylglycerol concentration for full-fat stimuli. This is less robust for fat-free versions of the same food. ► The functions of oral fat detection are poorly characterized, but may include, modulation of lipid trafficking in the enterocyte, detoxification of lipophilic cytotoxic compounds, appetite, energy intake and/or fat soluble nutrient absorption.
Section snippets
Gustatory detection of FFA
Dietary fats are clearly detected when in the oral cavity by tactile [30] and retronasal olfactory cues [31]. If there is a gustatory component as well, FFA are the most likely effective stimuli. There is no known or proposed receptor for triglyceride, the predominant form of lipid in the diet, as its ligand. A number of rodent studies indicate that esterified fatty acids are not effective stimuli [32], [33], [34], [35], [36]. Psychophysical studies indicate that humans can detect FFA with
Fatty acid signaling
Fatty acids are critical components of cell signaling processes through multiple mechanisms [7]. As integral components of cellular lipid membranes, they modulate cellular uptake of signaling compounds by diffusion and through channels. Additionally, the nature of fatty acids in lipid rafts determines the efficacy for docking of signaling proteins [6], [7]. Fatty acids are also precursors for hormones and substrates in signaling pathways [45]. Further, they are modulators of intracellular
Oral fat detection and lipid processing
Oral detection of dietary fats and fatty acids may be assessed by psychophysical methods, as noted above, or through measurement of biomarkers of lipid metabolism, most commonly, a change of serum triacylglycerol concentration [14], [15], [16], [18], [19], [20], [21], [22], [23], [24], [25]. It is hypothesized that oral exposure to fat leads to afferent signals carried by gustatory nerves to the nucleus of the solitary tract followed by reflexive efferent vagus activity that alters intestinal
Lipid storage in and mobilization from the GI tract
A number of studies indicate that ingestion of a high-fat meal leads to a greater post-prandial TAG concentration after ingestion of the subsequent meal; i.e., second-meal effect [15], [16], [64], [65], [66]. Increased release of pre-formed chylomicrons stored in the lamina propria, lacteals and/or lymph [15], [55], [67], [68] and increased hepatic VLDL production and secretion may be contributors [18]. However, contrary to popular views, accumulating evidence indicates that a substantive
Oral fat detection and post-prandial serum TAG concentrations
Multiple trials from different laboratories have demonstrated that oral stimulation alters post-prandial lipid concentrations [14], [15], [16], [18], [19], [20], [21], [22], [23], [24], [25], [55], [56]. An early study designed to examine the kinetics of vitamin A absorption noted that food intake after vitamin loading led to a rapid rise of plasma vitamin A concentrations [55] reflecting a rise of TAG since the vitamin is fat soluble. A follow-up controlled, modified-sham feeding trial (using
Post-prandial TAG concentration and risk for cardiovascular disease
Earlier assessments of the association between TAG concentrations and cardiovascular disease (CVD) focused on resting values, in large part, because they were viewed as less variable and more representative of lipid metabolism. Univariate analyses often revealed a positive association, but this was diminished in multivariate assessments. However, recognition that with increased eating frequency, people are effectively in a postprandial state much of the day, attention turned to the predictive
Functions of oral fat detection
One of the more perplexing questions related to the findings of enterocyte lipid storage and sensory mobilization of the pool concerns the function of this relationship. Evidence that elevated TAG is a risk factor for CVD suggests that the association poses a health risk, but this may only hold in the present environment. Beneficial roles would be predicted for the evolution and maintenance of such an integrated system. The following discussion speculates on possible functions with the intent
Intake
The first issue to address concerns the role of oral fat detection on fat ingestion as dietary fat is the likely primary source of lipid for the intestinal pool. Fat in foods may be detected by all human sensory systems, but each can lead to a different affective response. Fat is consumed in high quantity by many populations, in part, because it contributes a palatable sensory sensation. This is primarily attributable to its tactile properties (e.g., viscosity and lubricity) and delivery of
Fat soluble nutrient absorption
Vitamin A is a fat-soluble compound and is often used in clinical trials as a marker for lipid absorption. Effects of sensory stimulation on vitamin A absorption were described half a century ago through a series of studies prompted by a serendipitous observation [55]. Vitamin A palmitate mixed with corn oil was administered to 16 healthy individuals with normal vitamin A status, but five participants exhibited little absorption over the following 8 h period. During a trial, one of these
Facilitation of feeding via impaired leptin signaling
Leptin's role in appetite and feeding regulation has not been fully described. Most commonly, it is regarded as a satiety hormone that reduces eating frequency [80]. However, it is relatively ineffective in obese individuals, possibly due to limited transport across the blood brain barrier and access to its target sites [81]. This could be attributable to elevated circulating TAG which is common in the obese and inhibits such transport [82]. Alternatively, it may be that leptin functions more
Intestinal energy pool
The GI tracts of vertebrates adapt to wide variations of ingestive behavior [86]. Generally, it is an organ with high energy demands due to the rapid turnover of its cells, support of various transport systems and synthetic processes. In humans, it extracts over 25% of arterial oxygen while constituting only 5% of body weight [87]. Because of the high cost of its maintenance, down-regulation of its activity and mass between eating events could offer an adaptive advantage. This has been clearly
Appetite regulation
Although strong evidence indicates that total energy flux is the principal determinant of body weight, individual macronutrients make unique contributions [94]. Within the GI tract, fats are involved as signaling molecules and substrates. Starting in the oral cavity, isolated taste cells can act as endocrine cells and secrete an array of “satiety” hormones (e.g., GLP-1, glucagon, and PYY) following topical application of glucose [95]. Further, GLP-1 concentrations increase with glucose
Detoxification
The FFA that serve multiple vital functions in the body are also cytotoxic if not appropriately packaged and stored [117]. This is most apparent in tissues with limited fat storage capacity under conditions of high fat intake. Lipotoxicity manifests as insulin resistance in skeletal muscle, abnormalities of pancreatic insulin secretion and apoptosis in multiple organs, including the heart. Enterocytes are exposed to the greatest fluxes of fat and so are at particular risk for lipotoxicity and
Summary
Enterocytes are exposed to wide fluxes of lipids and must dampen these oscillations within themselves and for other tissues in the body, so that none is exposed to either too much or too little of a good (e.g., essential fatty acid) or bad (e.g., free fatty acid) thing. It is posited that this function is aided by an upstream signaling system, taste, that increasingly appears to be capable of detecting fatty acids of varying properties and relaying this information down the GI tract to
References (120)
- et al.
G protein-coupled receptors for free fatty acids
Cell Signal
(2006) - et al.
Taste signaling elements expressed in gut enteroendocrine cells regulate nutrient-responsive secretion of gut hormones
Am J Clin Nutr
(2009) Oro-sensory perception of dietary lipids: new insights into the fat taste transduction
Biochim Biophys Acta
(2009)The taste of fat elevates postprandial triacylglycerol
Physiol Behav
(2001)- et al.
Dynamics of fat absorption and effect of sham feeding on postprandial lipema
Gastroenterology
(2010) - et al.
Jejunal wall triglyceride concentration of morbidly obese persons is lower in those with type 2 diabetes mellitus
J Lipid Res
(2010) - et al.
Timing of vagal stimulation affects postprandial lipid metabolism in humans
Am J Clin Nutr
(2002) Oral fat exposure alters postprandial lipid metabolism in humans
Am J Clin Nutr
(1996)Oral exposure to butter, but not fat replacers elevates postprandial triacylglycerol concentration in humans
J Nutr
(2001)Oral fat exposure increases the first phase triacylglycerol concentration due to release of stored lipid in humans
J Nutr
(2002)
Effects of oral stimulation with fats on the cephalic phase of pancreatic enzyme secretion in esophagostomized rats
Physiol Behav
PROP taster status and oral fatty acid perception
Eat Behav
Polyunsaturated fatty acids and inflammatory processes: new twists in an old tale
Biochimie
The orphan G-protein-coupled receptor GPR 40 is activated by medium and long chain fatty acids
J Biol Chem
A dynamic, cytoplasmic triacylglycerol pool in enterocytes revealed by ex vivo and in vivo coherent anti-stokes Raman scattering imaging
J Lipid Res
Intestine-specific expression of acyl CoA:diacylglycerol acyltransferase 1 reverses resistance to diet-induced hepatic steatosis and obesity in Dgat1−/− mice
J Lipid Res
PAT proteins, an ancient family of lipid droplet proteins that regulate cellular lipid stores
Biochim Biophys Acta
Thematic review series: adipocyte biology. The perilipin family of structural lipid droplet proteins: stabilization of lipid droplets and control of lipolysis
J Lipid Res
Differential association of adipophilin and TIP47 proteins with cytoplasmic lipid droplets in mouse enterocytes during dietary fat absorption
Biochim Biophys Acta
Postprandial lipemia: the origin of an early peak studied by specific dietary fatty acid intake during sequential meals
Am J Clin Nutr
Intestinal synthesis and lymphatic secretion of apolipoprotein A-IV after cessation of duodenal fat infusion: mediation by bile
Biochem Biophys Acta
Intestinal absorption and lymphatic transport of a high ɤ-linoleic acid canola oil in lymph fistula Sprague–Dawley rats
J Nutr
Prolonged effects of modified sham feeding on energy substrate mobilization
Am J Clin Nutr
Tasting fat: cephalic phase hormonal responses and food intake in restrained and unrestrained eaters
Physiol Behav
Palatability and dietary restraint: effect on cephalic phase insulin release in women
Physiol Behav
Spontaneous insulin fluctuations and the preabsorptive insulin response to food ingestion in humans
Physiol Behav
Cephalic-phase insulin in obese and normal-weight men: relation to postprandial insulin
Metabolism
Cellular fatty acid uptake: a pathway under construction
Trends Endocrinol Metab
Relation between circulating leptin concentrations and appetite during a prolonged, moderate energy deficit in women
Am J Clin Nutr
Metabolic fate and function of dietary glutamate in the gut
Am J Clin Nutr
Regulation of C. elegans longevity by specific gustatory and olfactory neurons
Neuron
Plasma concentrations of regulatory peptides in obesity following modified sham feeding (MSF) and a liquid test meal
Regul Pept
Consumption of a high-fat diet alters the homeostatic regulation of energy balance
Physiol Behav
Nutrient utilization by cells isolated from rat jejunum, cecum and colon
J Nutr
Is there a fatty acid taste?
Annu Rev Nutr
Fat taste in humans: is it a primary
Taste preference for fatty acids is mediated by GPR40 and GPR120
J Neurosci
Fatty acids modulate toll-like receptor 4 activation through regulation of receptor dimerization and recruitment into lipid rafts in a reactive oxygen species-dependent manner
J Biol Chem
The membrane and lipids as integral participants in signal transduction: lipid signal transduction for the non-lipid biochemist
Adv Physiol Educ
International union of pharmacology. LXXI. Free fatty acid receptors FFA1, -2, and -3: pharmacology and pathophysiological functions
Pharmacol Rev
Free fatty acid receptors and drug discovery
Biol Pharm Bull
CD36 may determine our desire for dietary fats
J Clin Invest
Mobilisation of enterocyte fat stores by oral glucose in humans
Gut
Satiety and substrate mobilization after oral fat stimulation
Br J Nutr
Oral detection of short-, medium-, and long-chain free fatty acids in humans
Chem Senses
Oral fat exposure pattern and lipid loading effects on the serum triacylglycerol concentration of humans
Chemosens Percept
Hedonics and the lipemic response to oral fat exposure
Chem Senses
Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women
JAMA
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2019, Archives of Oral BiologyThe role of fatty acids and their endocannabinoid-like derivatives in the molecular regulation of appetite
2018, Molecular Aspects of MedicineCitation Excerpt :During a next meal this fat can be released, causing higher post-prandial TAG concentrations in plasma. This process might explain the ‘second meal effect’ sometimes observed (Mattes, 2011). De novo synthesis of fatty acids from carbohydrates, lactate or amino acids via acetyl-CoA primarily takes place in the liver and adipose tissue, to a lesser extent muscle tissue, and during lactation also in mammary glands.
Fatty acid translocase gene CD36 rs1527483 variant influences oral fat perception in Malaysian subjects
2017, Physiology and BehaviorThe influence of a high-fat meal on fat taste thresholds
2016, AppetiteEffects of food form on appetite and energy balance
2016, Food Quality and PreferenceCitation Excerpt :Blocking the CPIR leads to greater peak post-prandial plasma glucose concentrations and a prolonged elevation of circulating glucose (Calles-Escandon & Robbins, 1987; Lorentzen, Madsbad, Kehlet, & Tronier, 1987; Steffens, 1976). Many other examples of cephalic phase responses to oral stimulation could be cited such as bitterness evoking CCK release with implications for gastric emptying and appetite (Jeon, Seo, & Osborne, 2011; Sternini, 2007), saltiness moderating renal sodium clearance and possibly blood pressure levels (Akaishi, Shingai, Miyaoka, & Homma, 1991), or fat taste influencing circulating triglyceride concentrations and cardiovascular disease risk (Mattes, 1996b, 2011). Association of an item’s sensory properties with the post-ingestive consequences of consuming the item is an associative learning process that can influence dietary behavior.