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 3

Viral-mediated Ppg KO in the NTS.

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Viral-mediated Ppg KO in the NTS. (A) Schematic diagram showing deletion...
(A) Schematic diagram showing deletion of NTS Ppg by delivering mCherry-tagged AAVcre (AAVcre-mCherry) into the NTS of Ppgfl mice. (B and C) Representative images of GFP-IR in mice injected with AAVGFP (top panel, green) or mCherry-IR in AAVcre-mCherry (bottom panel, red) (B); GLP1-IR (purple) for similar mice is shown in C. All panels are representative of n ≥ 10 similar images. (D) Weekly body weight change on chow and HFD (measurements for each animal were normalized to its baseline weight). (E and F) Food intake is shown for the 8th week after surgery (E), and body composition is shown for 2 months after surgery (F). Data are from male animals; female body weight data are shown in Supplemental Figure 1I. Data are shown as mean ± SEM; D (n = 11–13), E (n = 6) and F (n = 5). All comparisons, P > 0.05 using repeated measures 2-way ANOVA with Sidak’s multiple comparisons test (D) and 2-tailed unpaired t test (E and F). AP, area postrema; cc, central canal. Scale bar: 150 μm.