Fig. 6: Intestinal GPR40 and GPR120 fat receptors activate the gut–brain axis.
a, We engineered knockout mice for three candidate fat receptors in the gut, and generated mice with every combination of these knockouts. We then recorded vagal responses to intestinal delivery of fat (10% LA) and sugar (500 mM Glu), and tested them for the development of fat and sugar preference. b, Heat maps depict z-score-normalized fluorescence traces from vagal neurons of SGLT1-knockout mice in response to intestinal delivery of fat (10% LA) and sugar (500 mM Glu). As previously shown, SGLT1 functions as the gut-to-brain sugar receptor4, and no vagal neurons responded to sugar in the knockout mice. However, responses to fat were unaffected (n = 174 out of 903 imaged neurons from 10 ganglia). Sglt1 is also known as Slc5a1. c, Heat maps illustrating the selective loss of fat responses in GPR40/GPR120 double-knockout (n = 51 out of 428 imaged neurons from 6 ganglia) and CD36/GPR40/GPR120 triple knockout (n = 44 out of 326 imaged neurons from 6 ganglia) mice. Note the normal responses to intestinal delivery of sugar in these knockout mice. See Extended Data Fig. 10 for imaging results for the other knockout lines. d, Bar graphs comparing vagal neurons responding to intestinal delivery of fat (10% LA) in control mice versus the various receptor knockouts (see Methods). Vagal responses were substantially affected only in the GPR40/GPR120 double-knockout (GPR40/GPR120, n = 7, P = 5 × 10−6) and in the triple knockout (TKO) (n = 6, P = 4 × 10−6) mice. Data are mean ± s.e.m.; statistics are shown in Methods. e, Knockout mice were tested for the development of fat preference. GPR40/GPR120 double knockouts (n = 7 mice, P = 0.81) and CD36/GPR40/GPR120 triple knockouts (n = 9 mice, P = 0.46) did not develop a preference for fat. White bars show initial preference and red bars show preference at the end of the 48 h test. All other combinations of knockouts developed a behavioural preference for fat, similar to control wild-type (WT) mice. Statistics are shown in Methods. Data are mean ± s.e.m. f, As expected, GPR40/GPR120 knockouts still develop preference for sugar. Wild type: n = 10 mice, P = 2.9 × 10−5; GPR40/GPR120: n = 9 mice, P = 8.0 × 10−5; TKO: n = 7 mice, P = 1.9 × 10−3. Data are mean ± s.e.m. Statistics are shown in Methods.
