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Fatty Acids and Fatty Acid-Sensing GPCRs


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Humans Can Use Smell to Detect Levels of Dietary Fat
Posted: January 27, 2014
New research from the Monell Center reveals humans can use the sense of smell to detect dietary fat in food. As food smell almost always is detected before taste, the findings identify one of the first sensory qualities that signals whether a food contains fat.
¡°The human sense of smell is far better at guiding us through our everyday lives than we give it credit for,¡± said senior author Johan Lundström, a cognitive neuroscientist at Monell. ¡°That we have the ability to detect and discriminate minute differences in the fat content of our food suggests that this ability must have had considerable evolutionary importance.¡±
The Monell researchers reasoned that fat detection via smell would have the advantage of identifying food sources from a distance. While previous research had determined that humans could use the sense of smell to detect high levels of pure fat in the form of fatty acids, it was not known whether it was possible to detect fat in a more realistic setting, such as food. In the current study, reported in the open access journal Plos One, the researchers asked whether people could detect and differentiate the amount of fat in a commonly consumed food product, milk.
In all three experiments, participants could use the sense of smell to discriminate different levels of fat in the milk. This ability did not differ in the two cultures tested, even though people in the Netherlands on average consume more milk on a daily basis than do Americans, the study found.
They also determined there was no relation between weight status and the ability to discriminate fat.
¡°We now need to identify the odor molecules that allow people to detect and differentiate differentiate levels of fat. Fat molecules typically are not airborne, meaning that they are unlikely to be sensed by sniffing food samples,¡± said lead author Sanne Boesveldt, a sensory neuroscientist. ¡°We will need sophisticated chemical analyses to sniff out the signal.¡±

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Fatty Acids and Fatty Acid-Sensing GPCRs

Several novel G-protein coupled receptors (GPCRs) have been identified in recent years using a variety of screens or as a result of the complete sequencing of the human genome that, subsequent to their characterization, were all shown to bind and be activated by free fatty acids and/or lipid molecules. In a search for novel galanin receptor subtypes a group of three tandemly encoded intronless genes were identified on chromosome 19q13.1 downstream of the CD22 gene. These three GPCRs were named as GPR40 (latter also identified as free fatty acid receptor 1, FFAR1), GPR41 (FFAR3), and GPR43 (FFAR2). Subsequent to their isolation and characterization GPR40 was shown to bind and be activated by medium- and long-chain free fatty acids, whereas, GPR41 and GPR43 were shown to be activated by short-chain free fatty acids.

GPR84 was identified as an orphan GPCR in a screen of differentially expressed genes in granulocytes. GPR119 and GPR120 were identified as a result of the human genome sequencing project and were shown to be members of the class A (rhodopsin-like) family of GPCRs. The class B scavenger receptor identified as CD36 is also involved in fatty acid transport across the plasma membrane and is also known as fatty acid translocase (FAT).

GPR40: GPR40 is abundantly expressed in pancreatic ¥â-cells and is also found in the gut in enteroendocrine cells. The preferred ligands for GPR40 are medium to long-chain (C12-C18) fatty acids that are saturated or unsaturated. GPR40 is coupled to a Gq protein that activates PLC¥ã upon ligand binding to the receptor. The activation of GPR40 in pancreatic ¥â-cells results in increased cytosolic Ca2+ via IP3-mediated release from the ER. The increased cytosolic Ca2+ can depolarize the ¥â-cell leading to an influx of additional Ca2+ leading to increased secretion of insulin. This is an important mechanism by which fatty acids enhance glucose-stimulated insulin secretion (GSIS).

GPR41 and GPR43 are activated by short-chain fatty acids (SCFAs) such as propionic acid, butyric acid, and pentanoic acid. Both of these receptors are expressed at highest levels in adipose tissue and immune cells but are also found expressed in enteroendocrine cells of the gut. The activation of GPR41 and GPR43 is involved in adipogenesis and the production of leptin by adipose tissue. In the gut, GPR41 and GPR43 are involved in responses to SCFAs derived from gut microbiota metabolism of complex carbohydrates.

Intestinal GPR41 plays a critical role in energy homeostasis and as well as control of feeding behaviors through the activated release of gut hormones such as PYY. Experiments with mice have shown that animals colonized in a sterile environment (i.e. free of gut microbiota) are resistant to high-fat diet induced obesity. However, when the guts of these sterile mice are colonized with saccharolytic bacteria from non-sterile mice they will become obese even on a diet of standard lab chow. However, in sterile GPR41 knock-out mice this effect of saccharolytic bacteria colonization is ablated. In addition, the normal increase in PYY secretion upon bacterial colonization is also significnatly reduced in GPR41 knock-out mice.

GPR84: GPR4 was originally shown to be activated by lipopolysaccharide (LPS) suggesting that medium-chain free fatty acids could be regulating inflammatory responses via interaction with GPR84. Subsequently it was demonstrated that GPR84 is a receptor for medium-chain free fatty acids such as capric acid (C10:0), undecanoic acid (C11:0), and lauric acid (C12:0). GPR84 is coupled to a pertussis toxin-sensitive Gi/o type G-protein. GPR84 is highly expressed in leukocytes and when the receptor is activated in the monocyte lineage there is an amplification of the LPS-stimulated IL-12 production. In macrophages that are influenced by local inflammatory conditions there is an increased level of expression of GPR84 in these cells.

GPR119: The fatty acid-sensing receptor, GPR119, is a Gs G-protein coupled receptor. GPR119 is expressed at the highest levels in the pancreas and fetal liver with expression also seen in the gastrointestinal tract, specifically the ileum and colon. GPR119 is a member of the class A family (rhodopsin-type) of GPCRs. GPR119 binds long-chain fatty acids including oleoylethanolamide (OEA), lysophosphatidylcholine (LPC), various lipid amides, and retinoic acid. The role of GPR119 in metabolic homeostasis is described in more detail below in the section on derivatives which focuses on OEA.
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The deorphanization of the free fatty acid (FFA) receptors FFA1 (GPR40), FFA2 (GPR43), FFA3 (GPR41), GPR84, and GPR120 has made clear that the body is capable of recognizing and responding directly to nonesterified fatty acid of virtually any chain length. Colonic fermentation of dietary fiber produces high concentrations of the short-chain fatty acids (SCFAs) acetate, propionate and butyrate, a process which is important to health. The phylogenetically related 7-transmembrane (7TM) receptors free fatty acid receptor 2 (FFA2) and FFA3 are activated by these SCFAs, and several lines of evidence indicate that FFA2 and FFA3 mediate beneficial effects associated with a fiber-rich diet, and that they may be of interest as targets for treatment of inflammatory and metabolic diseases. FFA2 is highly expressed on immune cells, in particular neutrophils, and several studies suggest that the receptor plays a role in diseases involving a dysfunctional neutrophil response, such as inflammatory bowel disease (IBD). Both FFA2 and FFA3 have been implicated in metabolic diseases such as type 2 diabetes and in regulation of appetite. More research is however required to clarify the potential of the receptors as drug targets and establish if activation or inhibition would be the preferred mode of action. The availability of potent and selective receptor modulators is a prerequisite for these studies. The few modulators of FFA2 or FFA3 that have been published hitherto in the peer-reviewed literature in general have properties that make them less than ideal as such tools, but published patent applications indicate that better tool compounds might soon become available which should enable studies critical to validate the receptors as new drug targets.

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GPR120: Obesity and Diabetes

GPR120 is specifically activated by long-chain non-esterified fatty acids (NEFAs) in particular in the intestines by ¥á-linolenic acid (ALA) an omega-3 polyunsaturated fatty acid (PUFA). Activation of GPR120 in the intestines results in increased GLP-1 secretion from enteroendocrine L cells. This results due to receptor-mediated activation of the intracellular signaling kinases ERK and PI3K.

GPR120 is highly expressed in adipose tissue, and proinflammatory macrophages. The high expression level of GPR120 in mature adipocytes and macrophages is indicative of the fact that GPR120 is likely to play an important role in biologic functions of these cell types. In contrast, negligible expression of GPR120 is seen in muscle, pancreatic ¥â-cells, and hepatocytes. Although not expressed at appreciable levels in hepatocytes expression of GPR120 is highly inducible in liver resident macrophage-like cells known as Kupffer cells. GPR120 can be activated with a synthetic agonist (GW9508) as well as omega-3 PUFAs. GPR120 is also expressed in enteroendocrine L cells of the gut. These are the cell types that express the incretin peptide hormone GLP-1. Previous work on GPR120 focused on the potential ability of this receptor to stimulate L cell GLP-1 secretion.
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Sense of taste informs the body about the quality of ingested foods. Five sub-modalities allowing the perception of sweet, salty, sour, bitter, and umami stimuli are classically depicted. However, the inborn attraction of mammals for fatty foods raises the possibility of an additional oro-sensory modality devoted to fat perception. During a long time, dietary lipids were thought to be detected only by trigeminal (texture perception), retronasal olfactory, and post-ingestive cues. This minireview analyses recent findings showing that the gustation also plays a significant role in dietary lipid perception.

Lipids represent around 40% of daily caloric intakes in Western diet while the nutritional recommandation is 10% lower. This chronic high-fat supply associated with a qualitative umbalance undoubtedtly increased the risk of obesity, and related diseases including type-2 diabetes, atherosclerosis, hypertension, and even cancers. Preference for fatty foods seems to be a common trait in
mammals. Rats, and mice spontaneously prefer lipid-enriched foods in a free-choice situation . Such a behavior might also to exist in humans. Indeed, data show that obese patients exhibit a higher preference for fatty foods than lean subjects [2, 3]. This last result raises the possiblity that an inappropriate orosensory perception of dietary lipids might influence obesity risk by impacting feeding behavior.
From an hedonic point of view, a specific appetite for lipids can be explained by positive fatassociated sensory qualities (fattiness, creaminess, flavour reinforcement). Spontaneous preference for lipids can also constitutes a physiological advantage especially when food is scarce by reason of nutritional roles of lipids, as high energy density nutrient, source of essential fatty acids, and carriers for fat soluble vitamins. Regulation of lipid intake is a
complex phenomenon involving both early orosensory stimuli (i.e. texture, odor, taste), and delayed post-ingestive signals. During a long time, the role of gustation in the oral fat perception has been negleted, dietary fat being thought to be detected only by trigeminal (texture perception), and retronasal olfactory cues [3]. However, recent evidences strongly suggest that the gustation also plays a significant role in the dietary lipid perception in rodents. Despite limited data, it is thought that a chemosensory system devoted to oral lipid perception can also exist in Humans.

5. A taste for fat in human : myth or reality ?
Data on the existence of a fat taste in humans are limited, and their interpretation uncertain by reason of a great individual variability. However, recent works of the Richard Mattes¡¯s team from Purdue University (USA) strongly suggest the existence in humans of an oral lipid perception at the origin of a fat signal contributing to the cephalic phase of digestion. Indeed, subjects submitted to a load with encapsuled oil (to avoid oral fat exposure) exhibited a higher
postprandial rise of blood triglycerides after a sham feeding with full-fat food than with a fat free version [26]. Since this event is independent of texture, and olfactory cues [26-29], it was hypothesized that an orosensory perception system for dietary lipids was involved. In line with this assumption, these authors have recently reported using a protocol excluding both olfactory, and texture stimuli that patients were able to detect 18C fatty acids of varying saturation [30]. Nevertheless, the mechanism by which oral perception of lipids takes place remains to be established in humans.

6. Conclusions
Physiological basis of the fat preference is going to be deciphered in the laboratory rodents. Lingual CD36 appears to play a significant role in this feeding behavior. Unpublished data from our Laboratory show that CD36 ¡°tastes¡± fatty foods through a classical gustatory pathway involving a Ca++-dependent stimulation of CD36-positive taste receptor cells, the gustarory nerve route (glossopharyngeal, and chorda tampany nerves), and the activation of gustatory area in the nucleus of solitary tract. Although this finding suggests that ¡°fatty¡± might constitute a basis taste, at least in mice, and rats, further experiments are required to explore the putative health impact of this orosensory system.

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