Background: GPR120 (FFAR4) is a GPCR activated by long chain fatty acids. Results: Palmitate-and DHA-stimulated glucagon secretion is markedly reduced from GPR120 KO islets. Conclusion: GPR120 is a nutrient sensor that is activated endogenously by both saturated and unsaturated long chain fatty acids. Significance: Targeting GPR120 for diabetes may impact glucose homeostasis in part through altering glucagon secretion and islet function.

The function of small intestinal monoacylglycerol lipase (MGL) is unknown. Its expression in this tissue is surprising because one of the primary functions of the small intestine is to convert diet-derived MGs to triacylglycerol (TG), and not to degrade them. To elucidate the function of intestinal MGL, we generated transgenic mice that over-express MGL specifically in small intestine (iMGL mice). After only 3 weeks of high fat feeding, iMGL mice showed an obese phenotype; body weight gain and body fat mass were markedly higher in iMGL mice, along with increased hepatic and plasma TG levels compared to wild type littermates. The iMGL mice were hyperphagic and displayed reduced energy expenditure despite unchanged lean body mass, suggesting that the increased adiposity was due to both increased caloric intake and systemic effects resulting in a hypometabolic rate. The presence of the transgene resulted in lower levels of most MG species in intestinal mucosa, including the endocannabinoid 2-arachidonoyl glycerol (2-AG). The results therefore suggest a role for intestinal MGL, and intestinal 2-AG and perhaps other MG species, in whole body energy balance via regulation of food intake as well as metabolic rate.

The ectopic deposition of fat in liver and muscle during obesity is well established, however surprisingly little is known about the intestine. We used the ob/ob mouse and C57BL6/J mice fed a high fat (HF) diet to examine the effects of obesity and the effects of HF feeding, respectively, on intestinal mucosal triacylglycerol (TG) accumulation. Male C57BL6/J (wild-type, WT) mice were fed low fat (LF; 10% kcal as fat) or HF (45%) diets, and ob/ob mice were fed the LF diet, for 3 weeks. In this time frame, the WT–HF mice did not become obese, enabling independent examination of effects of the HF diet and effects of obesity. Analysis of intestinal lipid extracts from fed and fasted animals demonstrated that the mucosa, like other tissues, accumulates excess lipid. In the fed state, mucosal triacylglycerol (TG) levels were threefold and fivefold higher in the WT–HF and ob/ob mice, respectively, relative to the WT–LF mice. In the fasted state, mucosa from ob/ob mice had threefold higher TG levels relative to WT–LF mucosa. q-PCR analysis of mucosal mRNA from fed state mice showed alterations in the expression of several genes related to both anabolic and catabolic lipid metabolism pathways in WT–HF and ob/ob mice relative to WT–LF controls. Fewer changes were found in mucosal samples from the fasted state animals. Remarkably, oral fat tolerance tests showed a striking reduction in the plasma appearance of an oral fat load in the ob/ob and WT–HF mice compared to WT–LF. Overall, the results demonstrate that the intestinal mucosa accumulates excess TG during obesity. Changes in the expression of lipid metabolic and transport genes, as well as reduced secretion of dietary lipid from the mucosal cells into the circulation, may contribute to the TG accumulation in intestinal mucosa during obesity. Moreover, even in the absence of frank obesity, HF feeding leads to a large decrease in the rate of intestinal lipid secretion.

Activation of peroxisome proliferator-activated receptors (PPARs) has been shown to have an important role in skin barrier function by regulating differentiation and lipid synthesis in keratinocytes. Oat (Avena sativa) has long been used as a soothing agent to relieve skin irritations, and the clinical benefits of topical oat formulations have been proven; however, the mechanistic understanding of oat's mode of action remains unknown. We investigated whether an oat lipid extract could activate PPARs and subsequently increase epidermal lipid synthesis and differentiation markers. Primary human epidermal keratinocytes and transformed cell lines were treated with PPAR agonists and oat lipid extracts to investigate the PPAR agonism. PPAR target genes and epidermal differentiation markers were analysed using quantitative real-time PCR and HPTLC analysis. Oat lipid extract demonstrated robust dual agonism for PPARα and PPARβ/δ, and increased direct PPAR target gene induction in primary human keratinocytes. In addition, oat oil treatment increased both receptor expression and, consistent with the literature on PPARs, oat oil treatment resulted in a significant upregulation of differentiation genes (involucrin, SPRRs and transglutaminase 1) and ceramide processing genes (β-glucocerebrosidase, sphingomyelinases 3 and ABCA12). Further, oat oil treatment in keratinocytes significantly increased ceramide levels (70%), suggesting a functional translation of PPAR activation by oat oil in keratinocytes. Taken together, these results demonstrate that oat lipids possess robust dual agonistic activities for PPARα and PPARβ/δ, increase their gene expression and induce differentiation and ceramide synthesis in keratinocytes, which can collectively improve skin barrier function.

Intestinal monoacylglycerol (MG) metabolism is well known to involve its anabolic reesterification to triacylglycerol (TG).We recently provided evidence for enterocyte MG hydrolysis and demonstrated expression of the monoacylglycerol lipase (MGL) gene in human intestinal Caco-2 cells and rodent small intestinal mucosa. Despite the large quantities of MG derived from dietary TG, the regulation of MG metabolism in the intestine has not been previously explored. In the present studies, we examined the mRNA expression, protein expression, and activities of the two known MG-metabolizing enzymes, MGL and MGAT2, in C57BL/6 mouse small intestine, as well as liver and adipose tissues, during development and under nutritional modifications. Results demonstrate that MG metabolism undergoes tissue-specific changes during development. Marked induction of small intestinal MGAT2 protein expression and activity were found during suckling. Moreover, while substantial levels of MGL protein and activity were detected in adult intestine, its regulation during ontogeny was complex, suggesting post-transcriptional regulation of expression. In addition, during the suckling period MG hydrolytic activity is likely to derive from carboxyl ester lipase rather than MGL. In contrast to intestinal MGL, liver MGL mRNA, protein and activity all increased 5-10-fold during development, suggesting that transcriptional regulation is the primary mechanism for hepatic MGL expression. Three weeks of high fat feeding (40% kcal) significantly induced MGL expression and activity in small intestine relative to low fat feeding (10% kcal), but little change was observed upon starvation, suggesting a role for MGL in dietary lipid assimilation following a high fat intake. sn-2-Monoacylglycerol (MG)2 is one of the major digestive products of dietary triacylglycerol (TG). Along with fatty acid, it is formed by the action of pancreatic triacylglycerol lipase (PTL) in the intestinal lumen, because PTL preferentially cleaves the sn-1 and 3 positions of TG (1). Both hydrolysis products are absorbed as monomers across the apical membrane of the intestinal epithelial cell (1, 2). The mechanism of sn-2-MG uptake into the enterocyte has been demonstrated to be a saturable function of the monomer concentration of sn-2-MG at both apical and basal lateral surfaces of the cell, suggesting carrier-mediated uptake (2, 3). At higher concentrations, a diffusional uptake pathway is also apparent (2, 3). After absorption, sn-2-MG is rapidly reincorporated into TG in the endoplasmic reticulum (ER) via the so-called monoacylglycerol acyltransferase (MGAT) pathway, which is catalyzed by two enzymes, MGAT2 and diacylglycerol acyltransferase (DGAT). Two DGAT isoforms (DGAT1 and 2) have been identified, and both are expressed in small intestine (4, 5). In addition to the MG pathway, the intestine can also synthesize TG via the glycerol-3-phosphate (G3P) pathway, which is the dominant TG synthetic pathway in other tissues such as adipose and liver (1). In the intestine, however, more ...

Aging is associated with the loss of facial subcutaneous fat and with increased abdominal subcutaneous fat. Site specific differences in adipocyte phenotype and/or gene expression may play a role in these age-related changes. In this study, we isolated and characterized human facial preadipocytes and investigated distinct metabolic properties such as a differentiation pattern in relation to abdominal preadipocytes. Subcutaneous preadipocytes were isolated from human facial and abdominal skin and cultured in the presence of differentiation factors including rosiglitazone, a known peroxisome proliferator-activated receptor gamma (PPAR-g) agonist, isobutyl-methyl xanthine (IBMX) and insulin. Differentiation was characterized microscopically and by quantitative real-time PCR. Unexpected superior adipogenic capacity of facial preadipocytes was observed; more facial preadipocytes differentiated in response to rosiglitazone than abdominal preadipocytes and facial preadipocytes retained their ability to differentiate through passage 11 compared with passage 5 for abdominal preadipocytes. Experiments confirmed a reduced lipolysis response in facial versus abdominal adipocytes after exposure to isoproterenol, which was consistent with the reduced b2-adrenergic receptor expression by 60% in the facial cells. The expression of other lipid metabolic gene markers was similar in both facial and abdominal adipocytes with the exception of b 3 -adrenergic receptor which was only found in abdominal adipose tissue. Gene profiling, by microarray analysis, identified that several HOX genes are robustly reduced in facial adipocytes compared to abdominal adipocytes, suggesting different characteristics between the 2 fat depots. These differences may have implications for development of treatments for facial fat loss during aging.

We recently demonstrated that, in addition to the well known anabolic metabolism of intestinal MG, MG hydrolytic activity and expression of the MG lipase (MGL) gene were present in rodent small intestine. The function of small intestinal MGL is unknown. We therefore generated transgenic mice (iMGL mice) that over‐expressed MGL specifically in small intestine using the intestinal fatty acid binding protein promoter. Marked induction of transgenic MGL mRNA was found in transgenic animals and intestinal specific expression of the transgene was confirmed. Western analysis and MGL activity measurements were also performed. Following 3 weeks of high fat feeding (40% Kcal), body weight gain and total fat pad weight were significantly increased in iMGL mice compared to non‐transgenic littermates. DXA measurements showed that body fat mass was significantly higher in the iMGL mice whereas lean mass was not altered. Triacylglycerol (TG) content of intestinal mucosa and liver were also increased in iMGL mice. Plasma TG levels in iMGL mice were high but free fatty acid and total cholesterol levels were not changed. The metabolism of 14C oleate and 3H monoolein in small intestinal mucosa were not substantially altered, although less labeled MG remained following in vivo incubation, likely due to the action of the MGL transgene. Food intake data showed that the iMGL mice were hyperphagic. Based on this phenotype, we hypothesize a role for intestinal MGL in whole body energy balance, possibly via regulation of food intake.

No abstract