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FFAR Out New Targets for Diabetes

2015; Cell Press; Volume: 21; Issue: 3 Linguagem: Inglês

10.1016/j.cmet.2015.02.015

1932-7420

Kacey J. Prentice, Michael B. Wheeler,

Diabetes and associated disorders

Dyslipidemia has long been associated with β cell dysfunction in the development of diabetes. Tang et al., 2015Tang C. Ahmed K. Gille A. Lu S. Gröne H.J. Tunaru S. Offermanns S. Nat. Med. 2015; 21: 173-177Crossref PubMed Scopus (205) Google Scholar have now revealed that β cell short-chain fatty acid receptors FFA2 and FFA3 are activated in an autocrine fashion and reduce insulin secretion in type 2 diabetes models. Dyslipidemia has long been associated with β cell dysfunction in the development of diabetes. Tang et al., 2015Tang C. Ahmed K. Gille A. Lu S. Gröne H.J. Tunaru S. Offermanns S. Nat. Med. 2015; 21: 173-177Crossref PubMed Scopus (205) Google Scholar have now revealed that β cell short-chain fatty acid receptors FFA2 and FFA3 are activated in an autocrine fashion and reduce insulin secretion in type 2 diabetes models. β cell dysfunction is the underlying cause of type 2 diabetes (T2D), characterized by insufficient insulin secretion to meet metabolic demands. Elevated glucose and fatty acids (FAs) have been associated with β cell failure through glucolipotoxicity (Poitout and Robertson, 2008Poitout V. Robertson R.P. Endocr. Rev. 2008; 29: 351-366Crossref PubMed Scopus (819) Google Scholar); however, the particular FAs mediating this process remain unknown. In vitro studies primarily use palmitic and oleic acid to mimic in vivo dyslipidemia, though the true lipid fingerprint of diabetes is much more complex. Recent work has confirmed that various metabolites elevated in diabetes play a contributing role in the development of β cell dysfunction (Newgard et al., 2009Newgard C.B. An J. Bain J.R. Muehlbauer M.J. Stevens R.D. Lien L.F. Haqq A.M. Shah S.H. Arlotto M. Slentz C.A. et al.Cell Metab. 2009; 9: 311-326Abstract Full Text Full Text PDF PubMed Scopus (2083) Google Scholar, Prentice et al., 2014Prentice K.J. Luu L. Allister E.M. Liu Y. Jun L.S. Sloop K.W. Hardy A.B. Wei L. Jia W. Fantus I.G. et al.Cell Metab. 2014; 19: 653-666Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar, Wang et al., 2013Wang T.J. Ngo D. Psychogios N. Dejam A. Larson M.G. Vasan R.S. Ghorbani A. O'Sullivan J. Cheng S. Rhee E.P. et al.J. Clin. Invest. 2013; 123: 4309-4317Crossref PubMed Scopus (288) Google Scholar), highlighting the complexity of this disorder. However, the source of these metabolites is largely thought to be from over-worked metabolic tissues, including liver, muscle, and adipose. In an intriguing recent article in Nature Medicine, Tang et al., 2015Tang C. Ahmed K. Gille A. Lu S. Gröne H.J. Tunaru S. Offermanns S. Nat. Med. 2015; 21: 173-177Crossref PubMed Scopus (205) Google Scholar have uncovered a role for short-chain FAs (SCFAs) produced by β cells in regulating glucose-stimulated insulin secretion (GSIS) through the SCFA receptors FFA2 and FFA3. The G protein-coupled receptors (GPCRs) FFA2 and FFA3 have been implicated as mediators of glucose tolerance because of their coupling to Gi proteins, which act to inhibit cAMP accumulation upon activation (Kebede et al., 2009Kebede M.A. Alquier T. Latour M.G. Poitout V. Diabetes Obes. Metab. 2009; 11: 10-20Crossref PubMed Scopus (99) Google Scholar). As cAMP accumulation is essential for GSIS, and particularly for incretin-stimulated GSIS, this made FFA2 and FFA3 prime targets to examine for a role in β cell dysfunction in T2D. Due to strong similarities in expression profile and function between the genes, loss of individual receptors is likely compensated for by the other, leading the researchers to adapt a double-knockdown/out strategy to examine the role of these receptors in GSIS. Tang et al., 2015Tang C. Ahmed K. Gille A. Lu S. Gröne H.J. Tunaru S. Offermanns S. Nat. Med. 2015; 21: 173-177Crossref PubMed Scopus (205) Google Scholar began by confirming co-expression of FFA2 and FFA3 in mouse and human primary β cells, and β cell lines. Functionality of these receptors was tested using the addition of the endogenous agonist acetate, which actively inhibited GLP-1-induced insulin secretion in a dose-dependent manner. Pre-treatment of the cells with the Gi inhibitor pertussis toxin, or knockdown of FFA2 and FFA3, blocked this effect, establishing FFA2 and FFA3 as inhibitors of insulin secretion. Importantly, accumulation of endogenously produced acetate, a SCFA produced through glycolysis, recapitulated this effect in β cells, suggesting autocrine inhibition of insulin secretion through FFA2 and FFA3 (Figure 1). To determine the role of FFA2 and FFA3 in glucose tolerance, Tang et al., 2015Tang C. Ahmed K. Gille A. Lu S. Gröne H.J. Tunaru S. Offermanns S. Nat. Med. 2015; 21: 173-177Crossref PubMed Scopus (205) Google Scholar generated mice globally lacking FFA2 and FFA3. Mice were phenotypically normal, with no difference in basal metabolic rate or energy expenditure under either normal chow or high-fat diet (HFD)-fed conditions. However, while no difference was observed in the glucose tolerance of FFA2 and FFA3 knockout mice under normal chow conditions, they exhibited a robust improvement in their glucose tolerance when challenged with HFD. The phenotype was replicated in a β cell-specific model of FFA2 and FFA3 deletion, indicating specificity of this effect in the β cell. Improved glucose tolerance correlated with enhanced plasma insulin concentrations, and decreased non-esterified FFA levels, consistent with increased insulin activity, though no change in insulin sensitivity. This suggests that the role of FFA2 and FFA3 in regulating insulin secretion is more prominent under diet-induced obese and diabetic conditions. Consistent with this observation, mice fed a HFD and humans with diabetes have increased circulating levels of acetate that correspond to increased expression of FFA2 and FFA3 in the islets of HFD mice. GLP1 plays a prominent role in potentiating GSIS, a function that is preserved in the islets of diabetic patients, making incretin agonists excellent therapeutics for T2D (Drucker, 2011Drucker D.J. Diabetes Care. 2011; 34: 2133-2135Crossref PubMed Scopus (20) Google Scholar). Enteroendocrine cells express both FFA2 and FFA3, and SCFAs are produced in large quantities through the breakdown of dietary fiber by the gut microbiome (Kebede et al., 2009Kebede M.A. Alquier T. Latour M.G. Poitout V. Diabetes Obes. Metab. 2009; 11: 10-20Crossref PubMed Scopus (99) Google Scholar). Thus, the authors investigated whether the effect on insulin secretion in vivo is mediated by altered incretin hormone release. Intestinal cell-specific deletion of FFA2 and FFA3 had no effect on insulin secretion, as mice challenged with a systemic bolus of acetate had no change in circulating insulin levels, compared to a dramatic drop in plasma insulin in β cell-specific FFA2 and FFA3 knockout mice. No difference in response to oral glucose challenge in the intestinal-specific knockouts was observed, suggesting that the effect of FFA2 and FFA3 on mediating insulin secretion is inherent to the β cell. As fewer than half of overweight and obese subjects develop diabetes in spite of dyslipidemia, ectopic fat accumulation, and massive insulin resistance, an inherent β cell dysfunction makes sense. Could these proteins represent novel therapeutic targets to enhance insulin secretion? Further investigation is warranted to determine the underlying mechanism of action of FFA2 and FFA3 in islets. While Gi-coupled GPCRs inhibit cAMP accumulation, they are also associated with increasing multiple factors known to stimulate GSIS from β cells (Kebede et al., 2009Kebede M.A. Alquier T. Latour M.G. Poitout V. Diabetes Obes. Metab. 2009; 11: 10-20Crossref PubMed Scopus (99) Google Scholar, Le Poul et al., 2003Le Poul E. Loison C. Struyf S. Springael J.Y. Lannoy V. Decobecq M.E. Brezillon S. Dupriez V. Vassart G. Van Damme J. et al.J. Biol. Chem. 2003; 278: 25481-25489Crossref PubMed Scopus (1099) Google Scholar). Furthermore, the effect of FFA2 and FFA3 deletion in isolated islets remains to be established. Acetate preferentially accumulates in the hypothalamus and directly regulates appetite through alterations in metabolism (Frost et al., 2014Frost G. Sleeth M.L. Sahuri-Arisoylu M. Lizarbe B. Cerdan S. Brody L. Anastasovska J. Ghourab S. Hankir M. Zhang S. et al.Nat. Commun. 2014; 5: 3611Crossref PubMed Scopus (879) Google Scholar). Thus, effects of hypothalamic deletion of FFA2 and FFA3 in both the whole body and β cell-specific knockout mice could mediate the observed improvements in glucose tolerance, as the rat insulin promoter (RIP) driving Cre may be active in these regions of the brain. Elevated circulating SCFAs in HFD-fed mice and diabetic humans implies an alternate source of SCFAs to induce β cell dysfunction, in addition to an autocrine effect. The role of the gut microbiome in generating SCFAs may come into play. While evidence exists to suggest that microbially produced SCFAs are protective against insulin resistance and glucose intolerance (Kimura et al., 2013Kimura I. Ozawa K. Inoue D. Imamura T. Kimura K. Maeda T. Terasawa K. Kashihara D. Hirano K. Tani T. et al.Nat. Commun. 2013; 4: 1829Crossref PubMed Scopus (902) Google Scholar), their effects may differ between β cells and insulin-sensitive tissues where FFA2 and FFA3 are also expressed. This represents an interesting avenue for future research. The article by Tang et al., 2015Tang C. Ahmed K. Gille A. Lu S. Gröne H.J. Tunaru S. Offermanns S. Nat. Med. 2015; 21: 173-177Crossref PubMed Scopus (205) Google Scholar identifies the SCFA receptors FFA2 and FFA3 as being expressed on β cells, and acting as important negative regulators of insulin secretion when stimulated by endogenous ligands, including acetate. Thus, FFA2 and FFA3 are novel potential therapeutic targets to specifically improve β cell dysfunction in T2D.