Expression of the Fatty Acid Receptor GPR120 in the Gut of Diet-Induced-Obese Rats and Its Role in GLP-1 Secretion

Abstract

Stimulation of the G protein coupled receptor GPR120 has been shown to have anti-inflammatory and insulin-sensitizing effects, to promote glucagon like peptide-1 (GLP-1) secretion, and to play a key role in sensing dietary fat and control energy balance. In a search for differentially expressed genes potentially involved in food intake and body-weight regulation we identified GPR120 to be differentially regulated in the intestine of selectively bred diet induced obese (DIO) and diet resistant (DR) rats. Subsequently we investigated the effect of GPR120 receptor stimulation with the long chain fatty acid alpha linolenic acid (ALA) on GLP-1 secretion in rats. Independent of diet (high or low fat), GPR120 expression showed a two-fold increase in the intestine of DIO compared to DR rats. In situ hybridization revealed a broad expression of GPR120 in the gut mucosa in both intestinal epithelial and endocrine cells. Using double in situ hybridization GPR120 mRNA did not appear to be enriched in preproglucagon expressing L-cells. In line with the anatomical data, ALA administration did not increase circulating GLP-1 levels. Our data shows a widespread expression of GPR120 in the gut epithelium and can not confirm a major role for GPR120 in the regulation of GLP-1 secretion. The broad expression of GPR120 in the gut epithelium supports reports indicating a putative role of GPR120 as a sensor of dietary fat.

Fish oil and flax seed oil supplemented diets increase FFAR4 expression in the rat colon

“…Interestingly, while agonism of FFAR4 with n-3 PUFA has clearly been shown to increase GLP-1 secretion from rodent and human intestinal L-cell lines [7–8], the in vivo effects of FFAR4 on GLP-1 secretion have been less poorly resolved. While some studies have shown that n-3 PUFA such as ALA and DHA increase plasma GLP-1 levels in vivo [7, 18], the physiological relevance of FFAR4 in this role have been challenged by other studies that have shown that FFAR4 agonism by ALA does not play a major role in increasing plasma GLP-1 levels in vivo in rats [13], as well as those that point to a contribution of the related FFAR1 in modulating the GLP-1 secretagogue effect of PUFA in vivo [19]. Here, we did not observe any alterations in GLP-1 concentrations in animals fed FO or FSO diets compared to those fed CON diets.…”

“…Meanwhile, epididymal adipose of mice fed high-fat diets with variable n-6:n-3 ratios ranging from 1:1 to 20:1 showed significantly lower levels of FFAR4 expression, and also had significantly higher levels of inflammatory mediators such as TNF-α and IL-10 compared to control-diet fed mice, suggesting that the n-6 and n-3 components of fats make important contributions toward both inflammation and expression of FFAR4 [12]. Similarly evidence exists in rats, where energy-dense, high-fat diets were found to increase expression of intestinal FFAR4 in a diet-induced obese (DIO) rat model as early as 6 months of age [13]. Interestingly, others have showed that the effects of high-fat diet on FFAR4 expression are tissue specific, as rats fed a high-fat diet for 12 weeks showed upregulation in FFAR4 expression in cardiac tissue and extensor digitorum longus (EDL) skeletal muscle, but not in liver or soleus skeletal muscle [14].…”

FFA4 receptor (GPR120): A hot target for the development of anti-diabetic therapies

“…In the gastrointestinal system, FFA4 receptor is expressed in the intestinal endocrine cell lines STC-1 and GluTag (Tsukahara et al, 2015), GIP-secreting K cells (Parker et al, 2009), stomach ghrelin-secreting SG-1 and MNG-1 cells (Lu et al, 2012), and dietary fat sensor epithelial cells (Paulsen et al, 2014). Previous studies have suggested that FFA4 receptor is involved in sensing the fat and regulation of hormone secretions such as GLP-1, GIP or CCK in these cells; however, the administration of the cpdA for a short duration (a newly identified synthetic FFA4 receptor agonist) did not cause significant GLP-1 secretion in enteroendocrine L cells (Oh da et al, 2014).…”

Non-Acidic Free Fatty Acid Receptor 4 Agonists with Antidiabetic Activity

“…[1][2][3][4][5][6][7] The receptor was proposed as a possible antidiabetic and antiobesity target for the first time in 2005 when it was reported to be expressed in the intestinal tract and activated by dietary free fatty acids to stimulate incretin secretion, 8 although this property of the receptor remains controversial. 9 FFA4 was subsequently found also to be expressed in macrophages, liver and adipose tissue, and to mediate antiinflammatory and insulin sensitizing effects. 10 The report that mice lacking FFA4 develop obesity, insulin intolerance and fatty liver when fed a high-fat diet and that a human population with a dysfunctional FFA4 variant has an increased risk of obesity supported a significant role of the receptor in metabolic diseases.…”