Leptin receptor–expressing nucleus tractus solitarius neurons suppress food intake independently of GLP1 in mice
Wenwen Cheng, Ermelinda Ndoka, Chelsea Hutch, Karen Roelofs, Andrew MacKinnon, Basma Khoury, Jack Magrisso, Ki Suk Kim, Christopher J. Rhodes, David P. Olson, Randy J. Seeley, Darleen Sandoval, Martin G. Myers Jr.
Wenwen Cheng, Ermelinda Ndoka, Chelsea Hutch, Karen Roelofs, Andrew MacKinnon, Basma Khoury, Jack Magrisso, Ki Suk Kim, Christopher J. Rhodes, David P. Olson, Randy J. Seeley, Darleen Sandoval, Martin G. Myers Jr.
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Research Article Endocrinology Metabolism

Leptin receptor–expressing nucleus tractus solitarius neurons suppress food intake independently of GLP1 in mice

Abstract

Leptin receptor–expressing (LepRb-expressing) neurons of the nucleus tractus solitarius (NTS; LepRbNTS neurons) receive gut signals that synergize with leptin action to suppress food intake. NTS neurons that express preproglucagon (Ppg) (and that produce the food intake–suppressing PPG cleavage product glucagon-like peptide-1 [GLP1]) represent a subpopulation of mouse LepRbNTS cells. Using Leprcre, Ppgcre, and Ppgfl mouse lines, along with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), we examined roles for Ppg in GLP1NTS and LepRbNTS cells for the control of food intake and energy balance. We found that the cre-dependent ablation of NTS Ppgfl early in development or in adult mice failed to alter energy balance, suggesting the importance of pathways independent of NTS GLP1 for the long-term control of food intake. Consistently, while activating GLP1NTS cells decreased food intake, LepRbNTS cells elicited larger and more durable effects. Furthermore, while the ablation of NTS Ppgfl blunted the ability of GLP1NTS neurons to suppress food intake during activation, it did not impact the suppression of food intake by LepRbNTS cells. While Ppg/GLP1-mediated neurotransmission plays a central role in the modest appetite-suppressing effects of GLP1NTS cells, additional pathways engaged by LepRbNTS cells dominate for the suppression of food intake.

Authors

Wenwen Cheng, Ermelinda Ndoka, Chelsea Hutch, Karen Roelofs, Andrew MacKinnon, Basma Khoury, Jack Magrisso, Ki Suk Kim, Christopher J. Rhodes, David P. Olson, Randy J. Seeley, Darleen Sandoval, Martin G. Myers Jr.

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Figure 4

Activation of LepRbNTS or GLP1NTS neurons suppressed food intake and body weight.

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Activation of LepRbNTS or GLP1NTS neurons suppressed food intake and bod...
(A and B) Representative images of DREADD-hM3Dq-mCherry (purple) and FOS-IR (green) in CNO-treated (1 mg/kg i.p., 2 hours) Ppgcre (A) and Leprcre (B) mice subjected to the injection of AAVhM3Dq into the GLP1NTS-Dq (PpgDq) and LepRbNTS-Dq (LepRbDq) mice, respectively. All panels are representative of n ≥ 3 similar images. AP, area postrema; cc, central canal. Scale bar: 150 μm. (C–E) Food intake following vehicle (Veh) or CNO (1 mg/kg i.p.) treatment of PpgDq and LepRbDq mice during refeeding following a fast (C; n = 5 and 8 in PpgDq and LepRbDq groups, respectively) or at the onset of the dark cycle (DC) on normal chow (D, n = 13 and 20 in PpgDq and LepRbDq groups, respectively) or HFD (E, n = 6 and 5 PpgDq and LepRbDq groups, respectively). (F and G) Daily food intake (F) and body weight relative to baseline (G) (n = 5–6 [F], 11–13 [G] in PpgDq and LepRbDq groups, respectively) during multiday treatment with CNO (1 mg/kg, i.p., bid). Data are from both sexes; for data separated by sex, see Supplemental Figure 1, J–N. Data are shown as mean ± SEM. Two-way ANOVA with Tukey’s multiple comparisons test was performed for each time point in each panel; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 for CNO groups compared with vehicle. #P < 0.05, ####P < 0.0001 for comparisons between CNO groups. Scale bar: 150 μm.