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• W2785655120 abstract "•Chronic PAHSA treatment improves insulin sensitivity in chow- and HFD-fed mice•PAHSAs activate GPR40, which mediates their augmentation of insulin secretion•GPR40 plays a role in the beneficial effects of PAHSAs on glucose homeostasis•GLP-1 receptor indirectly mediates PAHSA effects on glucose tolerance Palmitic acid hydroxystearic acids (PAHSAs) are endogenous lipids with anti-diabetic and anti-inflammatory effects. PAHSA levels are reduced in serum and adipose tissue of insulin-resistant people and high-fat diet (HFD)-fed mice. Here, we investigated whether chronic PAHSA treatment enhances insulin sensitivity and which receptors mediate PAHSA effects. Chronic PAHSA administration in chow- and HFD-fed mice raises serum and tissue PAHSA levels ∼1.4- to 3-fold. This improves insulin sensitivity and glucose tolerance without altering body weight. PAHSA administration in chow-fed, but not HFD-fed, mice augments insulin and glucagon-like peptide (GLP-1) secretion. PAHSAs are selective agonists for GPR40, increasing Ca+2 flux, but not intracellular cyclic AMP. Blocking GPR40 reverses improvements in glucose tolerance and insulin sensitivity in PAHSA-treated chow- and HFD-fed mice and directly inhibits PAHSA augmentation of glucose-stimulated insulin secretion in human islets. In contrast, GLP-1 receptor blockade in PAHSA-treated chow-fed mice reduces PAHSA effects on glucose tolerance, but not on insulin sensitivity. Thus, PAHSAs activate GPR40, which is involved in their beneficial metabolic effects. Palmitic acid hydroxystearic acids (PAHSAs) are endogenous lipids with anti-diabetic and anti-inflammatory effects. PAHSA levels are reduced in serum and adipose tissue of insulin-resistant people and high-fat diet (HFD)-fed mice. Here, we investigated whether chronic PAHSA treatment enhances insulin sensitivity and which receptors mediate PAHSA effects. Chronic PAHSA administration in chow- and HFD-fed mice raises serum and tissue PAHSA levels ∼1.4- to 3-fold. This improves insulin sensitivity and glucose tolerance without altering body weight. PAHSA administration in chow-fed, but not HFD-fed, mice augments insulin and glucagon-like peptide (GLP-1) secretion. PAHSAs are selective agonists for GPR40, increasing Ca+2 flux, but not intracellular cyclic AMP. Blocking GPR40 reverses improvements in glucose tolerance and insulin sensitivity in PAHSA-treated chow- and HFD-fed mice and directly inhibits PAHSA augmentation of glucose-stimulated insulin secretion in human islets. In contrast, GLP-1 receptor blockade in PAHSA-treated chow-fed mice reduces PAHSA effects on glucose tolerance, but not on insulin sensitivity. Thus, PAHSAs activate GPR40, which is involved in their beneficial metabolic effects. Type 2 diabetes (T2D) is a global epidemic (International Diabetes Federation, 2013International Diabetes Federation IDF Diabetes Atlas.Sixth Edition. International Diabetes Federation, 2013Google Scholar) characterized by hyperglycemia due to impaired islet function and insulin resistance in peripheral tissues. Despite advances in understanding the molecular mechanisms contributing to T2D and the development of new treatment modalities, the medical management of T2D remains inadequate (Aroda et al., 2012Aroda V.R. Henry R.R. Han J. Huang W. DeYoung M.B. Darsow T. Hoogwerf B.J. Efficacy of GLP-1R agonists and DPP-4 inhibitors: meta-analysis and systematic review.Clin. Ther. 2012; 34: 1247-1258.e22Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar). At present, many available treatment strategies including analogs of the incretin, glucagon-like peptide 1 (GLP-1), and dipeptidylpeptidase-4 inhibitors work primarily by increasing insulin secretion. Other effective agents promote glucose excretion (Campbell and Drucker, 2013Campbell J.E. Drucker D.J. Pharmacology physiology and mechanisms of incretin hormone action.Cell Metab. 2013; 17: 819-837Abstract Full Text Full Text PDF PubMed Scopus (930) Google Scholar, Meier, 2012Meier J.J. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus.Nat. Rev. Endocrinol. 2012; 8: 728-742Crossref PubMed Scopus (845) Google Scholar). However, there is still a need for effective and safe agents that enhance insulin sensitivity to improve glucose control and prevent diabetic complications. We discovered a novel class of endogenous lipids, branched fatty acid esters of hydroxy fatty acids (FAHFAs), with beneficial metabolic and anti-inflammatory effects (Yore et al., 2014Yore M.M. Syed I. Moraes-Vieira P.M. Zhang T. Herman M.A. Homan E.A. Patel R.T. Lee J. Chen S. Peroni O.D. et al.Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects.Cell. 2014; 159: 318-332Abstract Full Text Full Text PDF PubMed Scopus (500) Google Scholar). More than 16 FAHFA family members have been identified (Yore et al., 2014Yore M.M. Syed I. Moraes-Vieira P.M. Zhang T. Herman M.A. Homan E.A. Patel R.T. Lee J. Chen S. Peroni O.D. et al.Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects.Cell. 2014; 159: 318-332Abstract Full Text Full Text PDF PubMed Scopus (500) Google Scholar, Ma et al., 2015Ma Y. Kind T. Vaniya A. Gennity I. Fahrmann J.F. Fiehn O. An in silico MS/MS library for automatic annotation of novel FAHFA lipids.J. Cheminform. 2015; 7: 53Crossref PubMed Scopus (56) Google Scholar). Levels of one of the FAHFA family members, palmitic acid hydroxystearic acid (PAHSA), are markedly lower in serum and adipose tissue (AT) of insulin-resistant humans. PAHSA levels correlate strongly with insulin sensitivity as measured by euglycemic clamps in humans (Yore et al., 2014Yore M.M. Syed I. Moraes-Vieira P.M. Zhang T. Herman M.A. Homan E.A. Patel R.T. Lee J. Chen S. Peroni O.D. et al.Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects.Cell. 2014; 159: 318-332Abstract Full Text Full Text PDF PubMed Scopus (500) Google Scholar). Acute oral treatment with 5- or 9-PAHSA isomer in chow-fed and high-fat diet (HFD)-fed mice improves glucose tolerance and augments insulin and GLP-1 secretion in vivo. In vitro, PAHSAs directly enhance GLP-1 secretion from enteroendocrine cells and glucose-stimulated insulin secretion (GSIS) from human islets (Yore et al., 2014Yore M.M. Syed I. Moraes-Vieira P.M. Zhang T. Herman M.A. Homan E.A. Patel R.T. Lee J. Chen S. Peroni O.D. et al.Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects.Cell. 2014; 159: 318-332Abstract Full Text Full Text PDF PubMed Scopus (500) Google Scholar). Furthermore, PAHSAs have anti-inflammatory effects including decreasing AT inflammation in HFD mice and attenuating lipopolysaccharide-induced dendritic cell activation and cytokine production. Although we reported that a single dose of PAHSAs acutely improves glucose tolerance, whether PAHSAs have effects on insulin sensitivity has not been investigated. Therefore, the first aim of this study was to determine whether PAHSA treatment enhances insulin sensitivity in vivo, and the second aim was to determine whether the beneficial effects of PAHSAs are sustained with chronic treatment. The receptors responsible for PAHSA effects on insulin secretion and insulin action in vivo have not been identified. The G protein-coupled receptor (GPCR) GPR120 mediates PAHSA effects to enhance insulin-stimulated glucose transport in adipocytes (Yore et al., 2014Yore M.M. Syed I. Moraes-Vieira P.M. Zhang T. Herman M.A. Homan E.A. Patel R.T. Lee J. Chen S. Peroni O.D. et al.Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects.Cell. 2014; 159: 318-332Abstract Full Text Full Text PDF PubMed Scopus (500) Google Scholar), but PAHSAs are likely to activate other GPCRs because of their diverse actions in multiple tissues. Major pharmaceutical companies have had high-priority programs to screen for GPR120 and GPR40 activators to treat T2D. Molecules that activate both of these GPCRs with naturally evolved relative affinities may be more effective for T2D treatment than agonists for single receptors. Recent research has focused on identifying key agonists and receptors mediating nutrient-induced GLP-1 and insulin secretion. The long-chain fatty acid receptor GPR40 is the most abundant GPCR expressed in islet β cells and is also expressed on intestinal L-cells, where it contributes to GLP-1 release along with GPR120 (Itoh et al., 2003Itoh Y. Kawamata Y. Harada M. Kobayashi M. Fujii R. Fukusumi S. Ogi K. Hosoya M. Tanaka Y. Uejima H. et al.Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40.Nature. 2003; 422: 173-176Crossref PubMed Scopus (1243) Google Scholar, Edfalk et al., 2008Edfalk S. Steneberg P. Edlund H. Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion.Diabetes. 2008; 57: 2280-2287Crossref PubMed Scopus (469) Google Scholar). GPR40 activation augments GSIS and improves glycemia in rodent T2D models (Itoh et al., 2003Itoh Y. Kawamata Y. Harada M. Kobayashi M. Fujii R. Fukusumi S. Ogi K. Hosoya M. Tanaka Y. Uejima H. et al.Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40.Nature. 2003; 422: 173-176Crossref PubMed Scopus (1243) Google Scholar, Steneberg et al., 2005Steneberg P. Rubins N. Bartoov-Shifman R. Walker M.D. Edlund H. The FFA receptor GPR40 links hyperinsulinemia, hepatic steatosis, and impaired glucose homeostasis in mouse.Cell Metab. 2005; 1: 245-258Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar), and the GPR40 agonist TAK-875 lowers fasting and postprandial blood glucose and HbA1c levels in humans (Leifke et al., 2012Leifke E. Naik H. Wu J. Viswanathan P. Demanno D. Kipnes M. Vakilynejad M. A multiple ascending-dose study to evaluate safety, pharmacokinetics, and pharmacodynamics of a novel GPR40 agonist, TAK-875, in subjects with type 2 diabetes.Clin. Pharmacol. Ther. 2012; 92: 29-39Crossref PubMed Scopus (79) Google Scholar, Burant et al., 2012Burant C.F. Viswanathan P. Marcinak J. Cao C. Vakilynejad M. Xie B. Leifke E. TAK-875 versus placebo or glimepiride in T2D mellitus: a phase 2, randomised, double-blind, placebo-controlled trial.Lancet. 2012; 379: 1403-1411Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar). Because PAHSAs acutely augment GSIS directly from human islets (Yore et al., 2014Yore M.M. Syed I. Moraes-Vieira P.M. Zhang T. Herman M.A. Homan E.A. Patel R.T. Lee J. Chen S. Peroni O.D. et al.Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects.Cell. 2014; 159: 318-332Abstract Full Text Full Text PDF PubMed Scopus (500) Google Scholar), the third aim of this study was to determine whether PAHSAs activate GPR40 and whether this contributes to their beneficial effects in vivo. Here we show that PAHSAs directly activate GPR40, which is important for PAHSA effects on glucose homeostasis in both chow and HFD mice. Since PAHSAs augment GLP-1 secretion in insulin-resistant mice (Yore et al., 2014Yore M.M. Syed I. Moraes-Vieira P.M. Zhang T. Herman M.A. Homan E.A. Patel R.T. Lee J. Chen S. Peroni O.D. et al.Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects.Cell. 2014; 159: 318-332Abstract Full Text Full Text PDF PubMed Scopus (500) Google Scholar), we also investigated the role of the GLP-1 receptor (GLP-1R) in mediating PAHSA effects on glucose metabolism. GLP-1 potentiates insulin secretion and suppresses glucagon release (Holst, 2007Holst J.J. The physiology of glucagon-like peptide 1.Physiol. Rev. 2007; 87: 1409-1439Crossref PubMed Scopus (2235) Google Scholar), but its beneficial actions are not limited to the endocrine pancreas (Ayala et al., 2009Ayala J.E. Bracy D.P. James F.D. Julien B.M. Wasserman D.H. Drucker D.J. The glucagon-like peptide-1 receptor regulates endogenous glucose production and muscle glucose uptake independent of its incretin action.Endocrinology. 2009; 150: 1155-1164Crossref PubMed Scopus (87) Google Scholar, Christensen et al., 2015Christensen L.W. Kuhre R.E. Janus C. Svendsen B. Holst J.J. Vascular, but not luminal, activation of FFAR1 (GPR40) stimulates GLP-1 secretion from isolated perfused rat small intestine.Physiol. Rep. 2015; 3 (e12551)Crossref Scopus (74) Google Scholar, Villanueva-Peñacarrillo et al., 2011Villanueva-Peñacarrillo M.L. Martín-Duce A. Ramos-Álvarez I. Gutiérrez-Rojas I. Moreno P. Nuche-Berenguer B. Acitores A. Sancho V. Valverde I. González N. Characteristic of GLP-1 effects on glucose metabolism in human skeletal muscle from obese patients.Regul. Pept. 2011; 168: 39-44Crossref PubMed Scopus (17) Google Scholar). Here we show that the GLP-1R contributes to the beneficial PAHSA effects on insulin secretion and glucose tolerance, but not on insulin sensitivity, in chow mice. In addition, PAHSA-stimulated augmentation of GSIS in chow mice is directly mediated by GPR40, but their effects on GLP-1 secretion do not involve GPR40. Thus, PAHSAs improve glucose tolerance and insulin sensitivity in chow mice and these effects are sustained for 5 months. In HFD mice, glucose tolerance and insulin sensitivity are also improved by PAHSA treatment, but the effects are more modest. Furthermore, this study shows that PAHSAs directly activate GPR40, which contributes to their beneficial metabolic effects in mice on both chow and HFD. 5- and 9-PAHSA treatment for up to 18 weeks in chow mice had no effect on body weight, fat mass (Figure 1A), food intake, lean mass, serum triglycerides, or free fatty acid (FFA) levels (Figures S1A and S1B). Serum 5- and 9-PAHSA levels increased 2-fold with 2 months of treatment compared with vehicle mice (Figure 1B). After 5 months of treatment, only 9-PAHSA levels were elevated in serum (Figure 1B). However, 5- and 9-PAHSA levels were increased 1.5- to 3-fold in perigonadal (PG) and subcutaneous (SC) white AT (WAT) and brown AT. In liver, 9-PAHSA levels were elevated 2.5-fold in PAHSA-treated mice, and 5-PAHSA was detected even though this isomer was not found in liver of vehicle-treated mice as expected (Yore et al., 2014Yore M.M. Syed I. Moraes-Vieira P.M. Zhang T. Herman M.A. Homan E.A. Patel R.T. Lee J. Chen S. Peroni O.D. et al.Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects.Cell. 2014; 159: 318-332Abstract Full Text Full Text PDF PubMed Scopus (500) Google Scholar) (Figure 1B). 5- and 9-PAHSA levels were not increased in the pancreas or brain with chronic PAHSA treatment (Figure 1B). 5- and 9-PAHSA treatment improved insulin sensitivity as early as 13 days of treatment, and these effects were sustained for at least 5 months (Figure 1C). Glucose tolerance (Figure 1D) was also improved, similar to the effects reported with a single dose (Yore et al., 2014Yore M.M. Syed I. Moraes-Vieira P.M. Zhang T. Herman M.A. Homan E.A. Patel R.T. Lee J. Chen S. Peroni O.D. et al.Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects.Cell. 2014; 159: 318-332Abstract Full Text Full Text PDF PubMed Scopus (500) Google Scholar). Loss of first-phase insulin response to glucose is one of the major and early impairments of β cell function in T2D (Luzi and DeFronzo, 1989Luzi L. DeFronzo R.A. Effect of loss of first-phase insulin secretion on hepatic glucose production and tissue glucose disposal in humans.Am. J. Physiol. 1989; 257: E241-E246PubMed Google Scholar). Restoration of this response is associated with improvements in postprandial glucose excursions (Bruce et al., 1987Bruce D.G. Storlien L.H. Furler S.M. Chisholm D.J. Cephalic phase metabolic responses in normal weight adults.Metabolism. 1987; 36: 721-725Abstract Full Text PDF PubMed Scopus (91) Google Scholar). Chronic 5- and 9-PAHSA treatment enhances insulin secretion in response to glucose by 40% over vehicle-treated mice (Figure 1E, left panel). In PAHSA-treated mice, GLP-1 levels tended to be reduced at baseline but the stimulation in response to glucose was enhanced 225% over vehicle mice (Figure 1E, right panel). Thus, not only does an acute oral dose of PAHSAs improve first-phase insulin and GLP-1 responses to glucose, but this effect is maintained over 5 months without tachyphylaxis or β cell exhaustion. To confirm that the beneficial effects of PAHSAs on metabolic parameters are distinct from effects of ordinary FFAs, we performed similar studies with palmitate since PAHSAs are made up of palmitate and hydroxystearic acid. Palmitate treatment at the same dose used for PAHSAs did not have favorable effects on glucose tolerance, insulin tolerance, or glucose-stimulated insulin or GLP-1 secretion (Figures 1F–1I). In addition, unlike palmitate, which depletes islet insulin content with chronic exposure, PAHSA treatment of human islets for 72 hr results in sustained potentiation of GSIS and no loss of insulin content (data not shown). In addition, at the same concentration as PAHSAs (20 μM), palmitate did not augment GSIS in pancreatic MIN6 β cells (Figure S1C). This was not because of lower palmitate uptake into cells, since lipid uptake measured as the ratio of labeled PAHSA or 13C16-palmitate within the cell (high-density microsomes, low-density microsomes, and cytosol fractions) compared with plasma membranes was higher for palmitate than for PAHSAs (data not shown). We next investigated whether chronic PAHSA treatment reduces AT inflammation. PAHSA treatment reduced the total number of AT CD11c+ (pro-inflammatory) macrophages with no effect on AT CD206+ (anti-inflammatory) macrophages (Figures 1J and S1D). The total number of AT macrophages tended to be reduced with PAHSA treatment (Figure 1J) with no change in monocytes or neutrophils (Figures S1E and S1F). Moreover, PAHSA treatment reduced the number of pro-inflammatory interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) AT macrophages (Figure 1J). Together, these data indicate that chronic PAHSA treatment reduces AT inflammation, which could contribute to enhanced glucose homeostasis in chow mice. Since FFAs can induce insulin secretion through GPR40, we studied the role of GPR40 in mediating PAHSA effects. 9-PAHSA potentiated GSIS in isolated human islets, and this effect was completely reversed with the GPR40 antagonist, GW1100 (Figure 2A). Similarly, GPR40 knockdown in MIN6 cells completely reversed 9-PAHSA-potentiated GSIS without altering insulin secretion at low glucose (Figures 2B and S2A). Thus, both genetic and pharmacologic approaches indicate that PAHSAs augment GSIS by activating GPR40. To determine whether PAHSAs directly activate GPR40, we transfected HEK293 cells with mouse GPR40 and SRE-luc. 9-PAHSA dose-dependently activates GPR40 (Figure 2C). 5-PAHSA also activates GPR40 (Figure S2B). PAHSAs also directly activate human GPR40 (data not shown). 9-PAHSA-induced GPR40 activation was attenuated by GW1100 in a dose-dependent manner (Figure 2D). We next determined whether PAHSAs are full or selective GPR40 agonists. 9-PAHSA increased Ca+2 flux similar to the positive control linoleic acid, and GW1100 attenuated this effect (Figure 2E). However, 9-PAHSA had no effect on intracellular cyclic AMP (cAMP) levels (Figure 2F). Thus, PAHSAs are selective, not full, agonists for GPR40. We also tested whether GPR40 directly mediates PAHSA effects on GLP-1 secretion in STC-1 enteroendocrine cells. Both 5- and 9-PAHSAs augmented GLP-1 secretion in STC-1 cells by 1.5- to 2-fold, but GPR40 antagonism did not reduce this effect (Figure S2C). This suggests that PAHSA augmentation of GLP-1 secretion in enteroendocrine cells is independent of GPR40. To determine whether PAHSA effects on GSIS are mediated by GPR40 in vivo, we injected vehicle- and 5- and 9-PAHSA-treated chow mice with DC260126, a GPR40 antagonist. DC260126 attenuated the beneficial effects of PAHSAs on insulin sensitivity and glucose tolerance (Figures 2G and 2H compared with Figures 1C and 1D), but had no effect on vehicle-treated mice (Figures S2D–S2F). There was no effect of GPR40 inhibition on glycemia at baseline or 5 min after glucose gavage (Figures 2I and S2G). However, GPR40 inhibition lowered baseline insulinemia (30 min after DC260126) and completely blocked GSIS in PAHSA-treated mice (Figure 2I). In vehicle-treated mice, DC260126 also tended to impair GSIS (Figure S2G). The fact that DC260126 blocked the glucose effect on insulin secretion as well as the PAHSA effects may be because DC260126 inhibits an increase in intracellular Ca+2 (Hu et al., 2009Hu H. He L.Y. Gong Z. Li N. Lu Y.N. Zhai Q.W. Liu H. Jiang H.L. Zhu W.L. Wang H.Y. A novel class of antagonists for the FFAs receptor GPR40.Biochem. Biophys. Res. Commun. 2009; 390: 557-563Crossref PubMed Scopus (60) Google Scholar), possibly by modifying ligand-independent GPR40 activity (Milligan et al., 2017Milligan G. Shimpukade B. Ulven T. Hudson B.D. Complex pharmacology of free fatty acid receptors.Chem. Rev. 2017; 117: 67-110Crossref PubMed Scopus (154) Google Scholar). In PAHSA- and vehicle-treated mice, GPR40 inhibition did not affect glucose-stimulated GLP-1 secretion (Figures 2I and S2G). Thus, PAHSAs stimulate insulin secretion through GPR40 but their effects on GLP-1 secretion do not involve GPR40. The conclusion that DC260126 inhibition of PAHSA-mediated potentiation of insulin secretion in vivo (Figure 2I, middle panel) involves GPR40 is supported by the in vitro data using another GPR40 antagonist, GW1100 (Figure 2D), and genetic knockdown of GPR40 in β cells (Figure 2B). In terms of the specificity of DC260126, it had no effect on PAHSA activation of another lipid-responsive GPCR, GPR43 (data not shown). Specificity was also tested by Hu et al., 2009Hu H. He L.Y. Gong Z. Li N. Lu Y.N. Zhai Q.W. Liu H. Jiang H.L. Zhu W.L. Wang H.Y. A novel class of antagonists for the FFAs receptor GPR40.Biochem. Biophys. Res. Commun. 2009; 390: 557-563Crossref PubMed Scopus (60) Google Scholar using a calcium mobilization assay with GPR40 or melanin concentrating hormone receptor 2 (MCHR2), another GPCR of the same subtype Gαq/11. DC260126 dose-dependently inhibited FFA-induced GPR40 activation, but had no effect on MCHR2 activation by its ligand, melanin concentrating hormone (Hu et al., 2009Hu H. He L.Y. Gong Z. Li N. Lu Y.N. Zhai Q.W. Liu H. Jiang H.L. Zhu W.L. Wang H.Y. A novel class of antagonists for the FFAs receptor GPR40.Biochem. Biophys. Res. Commun. 2009; 390: 557-563Crossref PubMed Scopus (60) Google Scholar). Extensive testing for the specificity of DC260126 has not been done, but the lack of effect in vehicle-treated mice (Figures S2E and S2F) reduces the possibility of off-target effects. We also determined whether the effects of chronic PAHSA treatment in vivo are sustained in islets ex vivo. There was no augmentation of GSIS in islets from PAHSA-treated mice ex vivo compared with islets from vehicle mice (Figure S2H). This suggests that the continuous presence of PAHSAs is required to trigger the GPR40 activity. To determine whether PAHSA-induced improvements in glucose tolerance and insulin sensitivity are mediated through enhanced GLP-1 secretion, we injected vehicle- and 5- and 9-PAHSA-treated chow mice with the GLP-1R antagonist Exendin(9–39) (Ex(9–39)) (Figure 3A). Ex(9–39) completely reversed PAHSA-induced improvements in glucose tolerance (Figures 3B and S3A), but not insulin sensitivity (Figure 3C). In PAHSA-treated mice, GLP-1R blockade increased glycemia at baseline (30 min after Ex(9–39)) (Figures 3B–3D) and at 5 min after glucose administration (Figure 3D). In addition, Ex(9–39) treatment attenuated the PAHSA-mediated increase in GSIS. Ex(9–39) increased baseline GLP-1 levels but attenuated the increase in GLP-1 secretion above baseline in response to glucose (Figure 3D). In vehicle-treated mice, Ex(9–39) had no effect on baseline glucose (30 min after Ex(9–39)) or on glucose tolerance except at 45 min after glucose administration (Figure S3B). There was also no effect of Ex(9–39) on insulin sensitivity or on glycemia at baseline or 5 min post-glucose administration (Figures S3C and S3D). Furthermore, GLP-1R antagonism in vehicle-treated mice increased glucose-stimulated insulin and GLP-1 secretion (Figure S3D). This increase in GLP-1 secretion may be a compensatory response to GLP-1R blockade and likely stimulates insulin secretion. As expected, PAHSAs do not directly activate GLP-1R (Figure S3E), which is activated by peptides (GLP-1), not lipids. These data indicate that GLP-1 action is necessary for the full effects of PAHSAs on glucose tolerance, but not insulin sensitivity, and this may be due to PAHSA-mediated induction of GLP-1 secretion. These observations are consistent with a study in T2D people, in whom GLP-1 improves glycemic control by increasing insulin secretion and inhibiting glucagon secretion without improving insulin sensitivity (Vella et al., 2000Vella A. Shah P. Basu R. Basu A. Holst J.J. Rizza R.A. Effect of glucagon-like peptide 1(7-36) amide on glucose effectiveness and insulin action in people with type 2 diabetes.Diabetes. 2000; 49: 611-617Crossref PubMed Scopus (113) Google Scholar). 9-PAHSA treatment for 15–18 weeks via subcutaneous minipumps in HFD mice did not alter body weight, fat mass, lean mass, food intake, serum triglycerides, or FFA levels (Figures 4A, S4A, and S4B). 9-PAHSA levels were elevated ∼2-fold in serum and liver (Figure 4B) and ∼33%–42% in PG and SQ WAT compared with vehicle-treated HFD mice. 9-PAHSA levels were restored to chow mouse levels in serum and PG WAT but were not completely restored in SQ WAT (Figures 4B and 1B). Chronic PAHSA treatment in HFD mice improved insulin sensitivity (Figures 4C and S4C–S4F) and glucose tolerance (Figures 4D and S4E) compared with vehicle-treated HFD mice, and these effects were sustained for at least 4.5 months. We found that 9-PAHSA treatment (12 mg/kg/day) was more effective than a split dose of 5- and 9-PAHSA (6 mg/kg of each) in HFD mice (data not shown), although the combined treatment consistently lowered glycemia 5 hr after food removal (Figure S4D). Further studies showed 9-PAHSA lowered glycemia at 5 min post-glucose in HFD mice compared with vehicle-treated HFD mice with similar insulin levels (Figure 4E), supporting enhanced insulin sensitivity. Also in support of this, chronic 9-PAHSA treatment in HFD mice prevented the increase in islet mass seen in vehicle HFD mice (Figure 4F). This suggests that the same insulin levels are more efficient in lowering glucose in PAHSA HFD mice and that expansion of islet mass is not necessary. In contrast to PAHSA-treated chow mice (Figure 1E), PAHSA treatment in HFD mice did not enhance glucose-stimulated insulin or GLP-1 secretion compared with vehicle HFD mice (Figure 4E), but similar insulin levels lowered glucose more in PAHSA HFD mice. Thus, the beneficial PAHSA effects on glucose homeostasis in HFD mice are independent of changes in glucose-stimulated insulin or GLP-1 secretion and appear to involve increased insulin sensitivity. Expression of tnf-α in PG WAT was lower in PAHSA-treated HFD mice compared with vehicle-treated HFD mice (Figure 4G). This indicates that reduced WAT inflammation may contribute to the enhanced glucose homeostasis in PAHSA-treated HFD mice. Overall, the beneficial effects of PAHSAs are more moderate in HFD mice than in chow mice. This may be in part due to lack of full restoration of SQ WAT PAHSA levels. Since PAHSA beneficial effects on glucose homeostasis in chow mice are in part mediated by GPR40 (Figures 2G and 2H), we studied the role of GPR40 in mediating PAHSA effects in HFD mice. DC260126, a GPR40 antagonist, reversed PAHSA improvements on insulin (ITT) and glucose tolerance tests (GTT) in HFD mice (Figures 4H and 4I), but had no effect in vehicle HFD mice (Figures S4E and S4F). This effect of GPR40 inhibition in PAHSA HFD mice is mainly due to reversing PAHSA effects on lowering glycemia at time “0 min” of the oral GTT (OGTT) and ITT (Figures 4H, 4I, S4G, and S4H). These data suggest that GPR40 mediates at least some of the beneficial effects of PAHSAs in HFD mice, similar to the effects in chow mice. Prior to this study, we had investigated only acute effects of PAHSAs on glucose homeostasis, primarily with a single dose (Yore et al., 2014Yore M.M. Syed I. Moraes-Vieira P.M. Zhang T. Herman M.A. Homan E.A. Patel R.T. Lee J. Chen S. Peroni O.D. et al.Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects.Cell. 2014; 159: 318-332Abstract Full Text Full Text PDF PubMed Scopus (500) Google Scholar). Furthermore, we did not report data on insulin sensitivity. A major advance of this study is demonstrating that PAHSAs enhance insulin sensitivity. This is important because there is a major unmet medical need for safe insulin-sensitizing agents. Currently there are no anti-diabetic drugs that are primarily insulin-sensitizing except thiazolidinediones, which have adverse effects. Safe insulin-sensitizing agents could be used to prevent and treat insulin resistance, T2D, and cardiovascular complications. Since serum PAHSA levels correlate highly with insulin sensitivity in humans, and PAHSA levels are reduced in serum and SQ WAT of insulin-resistant people and HFD mice, we designed the current study to restore circulating and tissue PAHSA levels within the physiologic range (Yore et al., 2014Yore M.M. Syed I. Moraes-Vieira P.M. Zhang T. Herman M.A. Homan E.A. Patel R.T. Lee J. Chen S. Peroni O.D. et al.Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects.Cell. 2014; 159: 318-332Abstract Full Text Full Text PDF PubMed Scopus (500) Google Scholar). Although we achieved this in chow mic" @default.
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• W2785655120 title "Palmitic Acid Hydroxystearic Acids Activate GPR40, Which Is Involved in Their Beneficial Effects on Glucose Homeostasis" @default.
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