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A leptin–BDNF pathway regulating sympathetic innervation of adipose tissue

Abstract

Mutations in the leptin gene (ob) result in a metabolic disorder that includes severe obesity1, and defects in thermogenesis2 and lipolysis3, both of which are adipose tissue functions regulated by the sympathetic nervous system. However, the basis of these sympathetic-associated abnormalities remains unclear. Furthermore, chronic leptin administration reverses these abnormalities in adipose tissue, but the underlying mechanism remains to be discovered. Here we report that ob/ob mice, as well as leptin-resistant diet-induced obese mice, show significant reductions of sympathetic innervation of subcutaneous white and brown adipose tissue. Chronic leptin treatment of ob/ob mice restores adipose tissue sympathetic innervation, which in turn is necessary to correct the associated functional defects. The effects of leptin on innervation are mediated via agouti-related peptide and pro-opiomelanocortin neurons in the hypothalamic arcuate nucleus. Deletion of the gene encoding the leptin receptor in either population leads to reduced innervation in fat. These agouti-related peptide and pro-opiomelanocortin neurons act via brain-derived neurotropic factor-expressing neurons in the paraventricular nucleus of the hypothalamus (BDNFPVH). Deletion of BDNFPVH blunts the effects of leptin on innervation. These data show that leptin signalling regulates the plasticity of sympathetic architecture of adipose tissue via a top-down neural pathway that is crucial for energy homeostasis.

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Fig. 1: The effects of leptin on sympathetic innervation of adipose tissue, thermogenesis and lipolysis in leptin-deficient ob/ob mice.
Fig. 2: Leptin signals centrally through the ARC to regulate sympathetic innervation of subcutaneous adipose depots.
Fig. 3: AGRP and POMC neurons in the ARC mediate leptin-dependent sympathetic innervation of adipose tissue.
Fig. 4: BDNFPVH neurons regulate sympathetic innervation downstream of the ARC.

Data availability

The data that support the findings of this study are available from the corresponding authors upon reasonable request. Requests for reagents should be directed to J.F. Source data are provided with this paper.

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Acknowledgements

We thank all members of the Friedman lab for discussions and comments on the project, especially L. Pomeranz for providing PRV virus and K. Hedbacker for breeding ob/ob mice; Rockefeller BIRC for microscopy; C. H. Choi for help with metabolic home cages; F. Marchildon for help with Clark electrode measurements; and A. Ilanges, Z. Wu and P. Muller for suggestions on experiments. This work was supported by the JPB Foundation. X.Y. and K.H.L. are supported by fellowships from the Helen Hay Whitney Foundation.

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Authors

Contributions

P.W. and K.H.L. designed and performed all experiments with input from J.F. unless otherwise stated. J.F., P.W. and K.H.L. also analysed data and wrote the manuscript. M.S., P.W. and K.H.L. performed and analysed the data for measuring temperature following cold exposure in Fig. 1b, c. M.W. assisted P.W. and K.H.L. with experiments shown in Figs. 24. D.A.M. and K.R. performed and analysed data for sympathetic nerve recordings. X.Y. designed CRISPR constructs and generated their AAVs. J.C. performed SCG culture and advised on SNS quantification. D.K. assisted K.H.L. on the BDNF i.c.v. experiment. C.K. assisted with BDNF RNAscope experiments and generating reagents for Fig. 4. P.C. provided input on experimental design and data interpretation.

Corresponding authors

Correspondence to Ken H. Loh or Jeffrey Friedman.

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Competing interests

J.F. receives royalty payments for the sale of leptin through the Rockefeller University as part of its policy for distributing the proceeds for inventions to the inventors.

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Extended data figures and tables

Extended Data Fig. 1 ob/ob mice have thermogenesis and lipolysis defects.

a, Relative basal UCP1 protein levels in BAT of ob/ob mice compared to WT age matched control mice by western blotting. Protein levels are normalized to vinculin protein (n = 4 for WT, n = 5 for ob/ob). b, c, Relative basal p-HSL to HSL protein levels before and after 36 h fast in WT mice (b; n = 5 per group), ob/ob mice (c; n = 6 per group). d, e, Western blot quantified in a is shown in d, and b, c in e. Data show mean ± SEM. Significant differences between treatments calculated using Student’s two-tailed, unpaired t-test. Gels are cropped to show representative lanes used for quantification. Source data

Extended Data Fig. 2 Differences in thermogenesis and lipid mobilization following acute and chronic leptin treatment of ob/ob mice.

Supporting data for Fig. 1. a, Serum leptin levels measured by leptin ELISA from mice treated as in Fig. 1b–d (n = 6 for WT and Acute leptin, n = 7 for ob/ob, n = 5 for Chronic leptin). b, Representative coronal hypothalamic arcuate nucleus brain sections of mice from groups shown in (Fig. 1a), immunolabelled for p-STAT3 (in green) and DAPI (in blue). Scale bar, 100 μm. c, Thermographic camera images of mice assayed in Fig. 1b, c following cold challenge for 2 h. White arrow indicates BAT. d, Tail temperature as measured by thermographic camera, of mice treated as in Fig. 1b, c before (left panel) and after cold exposure for 2 h (right panel). Both WT and chronic leptin treated ob/ob mice exhibit lower tail temperatures, consistent with findings in ref. 4 (n = 6 for ob/ob PBS, n = 7 for all other groups). e, Western blots showing UCP1 and vinculin levels quantified in Fig. 1d. f, Relative mRNA levels of known thermogenesis genes in BAT following 4 h of cold exposure, as measured by qPCR (n = 4 for Chronic leptin, n = 5 for all other groups). g, Western blot showing p-HSL and HSL levels as quantified in Fig. 1e. Data show mean ± SEM, significant differences between treatments calculated using Student’s two-tailed, unpaired t-test. Gels are cropped to show representative lanes used for quantification. Source data

Extended Data Fig. 3 Defects in SNS innervation in adipose tissue.

Supporting data for Fig. 1ad, TH immunolabelling in iWAT and BAT, of 3-week old ob/ob (a, b) or 5-week old ob/ob (c, d) mice with age matched WT controls shown on left. e, Zoomed in optical sections of iWAT (visualized as by iDISCO) from 14-day chronic leptin treated ob/ob mice, WT age-matched control mice, or ob/ob mice treated with PBS control. Green boxes indicate parenchymal SNS innervation. Yellow arrows showing SNS innervation colocalizing with vasculature as marked by anti-CD31. f, TH and beta-tubulin 3 immunolabelling in delipidated BAT sections from ob/ob mice treated with 400 ng h−1 leptin (top) or PBS (bottom) for 14 days. g, Western blots of TH protein, PGP9.5 protein and loading control vinculin in iWAT. Quantification of relative levels of TH protein (left) and PGP9.5 protein (right) in iWAT normalized to vinculin (n = 5 for ob/ob+Leptin, n = 9 for all other groups). h, Western blots of TH protein and loading control vinculin in BAT. Quantification of relative levels of TH in BAT normalized to vinculin (n = 4 for WT, n = 5 for all other groups). Scale bar, 1 mm (ac); 100 μm (b, d, f); 200 μm (e). Data show mean ± SEM, significant differences between treatments calculated using Student’s two-tailed, unpaired t-test. Gels are cropped to show representative lanes used for quantification. Source data

Extended Data Fig. 4 Physiology of pair-fed ob/ob mice, leptin treatment time course and functional implications of restoring innervation.

Supporting data for Fig. 1a, Body weight over 14 days of ob/ob mice treated with leptin (red line), pair-fed to leptin treated ob/ob (orange line) or PBS treated ob/ob controls (blue line) (n = 3 for ob/ob, n = 4 for all other groups). b, Body fat composition of mice as measured by MRI (n = 3 for WT and ob/ob, n = 4 for all other groups). c, Quantification of images shown in Fig. 1h performed as described in ref. 10 and within the Methods section. (n = 3 per group). d, Quantification of images shown in Fig. 1i (n = 3 for ob/ob, n = 4 for all other groups). e, f, BAT (e) and core body (f) temperature of mice pair fed to 14-day leptin treated ob/ob mice as in Fig. 1a, following cold challenge (n = 7 for all groups except ob/ob given PBS, n = 6). Note that leptin treated ob/ob (red line) and PBS treated ob/ob (blue line) data shown here are the same as in Fig. 1b, c. g, 14-day subcutaneous leptin treatment reduced body weight in ob/ob mice (n = 3 for 0 day, n = 4 for all other groups). h, i, Sympathetic innervation density visualized by TH immunolabelling in iWAT (h) and BAT (i) in ob/ob mice was restored to levels similar in WT. Quantification of the images presented in Fig. 1j, k. j, k, ob/ob mice treated with PBS, 400 ng leptin for 2 weeks or 400 ng leptin for 2 weeks followed by leptin withdrawal for 3 weeks to allow mice to regain body weight until above 50 g, TH immunolabelling is visualized in iWAT (j; n = 4 per group) and BAT (k; n = 3 for Leptin withdraw, n = 4 for all other groups). l, Sympathetic nerve activity into BAT measured by electrophysiology for ob/ob mice provided chronic leptin treatment or PBS controls like in Fig. 1a. Relative increase in BAT SNA following cooling of mice. (n = 6 for PBS; n = 8 for Chronic leptin). m, n, O2 consumption measured by a Clark electrode of BAT (m) or iWAT (n) explants from wild type, ob/ob mice following 14-day leptin treatment, PBS control or ob/ob mice pair fed to leptin treated ob/ob group (n = 5 per group). Scale bar, 1 mm (h, j); 100 μm (i, k). Data show mean ± SEM, significant differences between treatments calculated using two-way ANOVA (a, e, f, l), or Student’s two-tailed, unpaired t-test (all other panels). Source data

Extended Data Fig. 5 Leptin signals through the ARC to regulate SNS innervation in subcutaneous adipose depots.

Supporting data for Fig. 2a, Average body weight of ob/ob mice from Fig. 2a after 14-day i.c.v. leptin or vehicle control (n = 4 per group). b, Leptin has negligible effects on the nerve growth of cultured superior cervical ganglia neurons. Dissociated cultured sympathetic ganglia treated with either NGF (10 ng/μl) only, leptin (100 ng/mL) only or both. Controls received neither factor. After 48 h, sympathetic neurons were fixed with 2% PFA in PBS, permeabilized and stained with anti-tyrosine hydroxylase antibody. c, To identify the first order neurons innervating adipose depots, cholera toxin B subunit (CTB) conjugated with Alexa 488 was injected into adipose depots. Once taken up by sympathetic axons it is transported to the cell bodies of sympathetic post-ganglionic neurons (bottom row). 2nd and subsequent order neurons were traced by injecting PRV expressing GFP into adipose depots which travelled retrogradely to infect sympathetic pre-ganglionic neurons in the IML before entering the brain (top row). d, Table of brain regions infected by PRV from adipose depots (additional data supporting Fig. 2c) over 4-7 days. Red text denotes regions overlapping with LepR-tdTomato neurons. e, 8 weeks post-surgery of AAV-GFP-Cre delivery into brain regions shown in Fig. 2d, 3 mg/kg IP leptin induced p-STAT3 signalling in indicated area was assessed to evaluate LepR deletion. Injection of AAV-GFP-Cre in indicated area leads to depletion of p-STAT3 (bottom row), compared with the same region in brain sections from the other two groups where LepR is deleted elsewhere (top row). f, g, Body weight progression (f) and daily food intake (g) of mice treated as in Fig. 2d (n = 6 for DMH, n = 5 for ARC or MPO). Daily food intake of each mouse was calculated as an average of 3 consecutive days. h, AAV-GFP-Cre injection (bottom row) in ARC of LepRfl/fl mice reduced leptin induced p-STAT3 signalling compared to AAV-GFP injected controls (top row). Quantification of imaging data shown on the right (n = 4 per group). i, j, Body weight progression (n = 7 per group) (i) and daily food intake (j) of mice treated as in Fig. 2g, h (n = 7 per group). Daily food intake of each mouse was calculated as an average of 3 consecutive days. k, Serum leptin level of LepRfl/fl mice 8 weeks post-surgery of the AAV-GFP-Cre or AAV-GFP injection (n = 6 for AAV-GFP, n = 5 for AAV-GFP-Cre). l, m, BAT temperature (l) and core temperature (m) of LepRfl/fl mice 8 weeks post-surgery of AAV-GFP-Cre or AAV-GFP injection, following cold exposure to 4 °C (n = 6 for AAV-GFP, n = 4 for AAV-GFP-Cre). n, Body weight progression of WT mice fed on 60% HFD (red) compared to those fed on standard chow (blue) for 4 months (n = 5 per group). o, Body weight progression of mice fed on 60% HFD (n = 5 per group except for 2 month HFD, n = 4). p, q, TH immunolabelling visualized in iWAT (p) and BAT (q) of age matched ob/ob mice (left) compared to WT mice fed on 60% HFD for 4 months (right). Graphs on right show quantification of images (n = 4 per group). Scale bar, 1 mm (p); 100 μm (c, e, h, q). Data shows mean ± SEM, significant differences between treatments calculated using two-way ANOVA (f, i, ln), or Student’s two-tailed, unpaired t-test (all other panels). Source data

Extended Data Fig. 6 AGRP and POMC neurons in the ARC regulate leptin-dependent sympathetic innervation changes in adipose tissue.

Supporting data for Fig. 3a, b, Body weight progression (n = 11 per group) (a) and daily food intake (n = 11 for sgCtrl, n = 10 for sgLepR) (b) of AGRP-IRES-Cre::LSL-Cas9-GFP mice treated as in Fig. 3f, g. Daily food intake of each mouse was calculated as an average of 3 consecutive days. c, Serum leptin level of AGRP-IRES-Cre::LSL-Cas9-GFP mice 12 week post-surgery of the gRNA injection (n = 4 for sgCtrl, n = 5 for sgLepR). d, e, BAT temperature (d) and core temperature (e) of AGRP-Cre::LSL-Cas9-GFP mice from Fig. 3f, g, following cold exposure at 4 °C for 4 h (n = 10 for sgCtrl, n = 11 for sgLepR). f, g, Body weight progression (f) and daily food intake (g) of POMC-Cre::LSL-Cas9-GFP mice treated as in Fig. 3h, i (n = 11 for Cre-, n = 9 for Cre+). Daily food intake of each mouse was calculated as an average of 3 consecutive days. h, Serum leptin level of POMC-Cre::LSL-Cas9-GFP mice 12 week post-surgery of AAV-gRNA injection (n = 4 for Cre-, n = 5 for Cre+). i, j, BAT temperature (i) and core temperature (j) of POMC-Cre::LSL-Cas9-GFP mice treated as in Fig. 3h, i following cold exposure at 4 °C for 4 h (n = 11 for Cre-, n = 9 for Cre+). Data show mean ± SEM, significant differences between treatments calculated using two-way ANOVA (a, df, i, j), or Student’s two-tailed, unpaired t-test (b, c, g, h). Source data

Extended Data Fig. 7 BDNFPVH regulates sympathetic innervation downstream of leptin signalling.

Supporting data for Fig. 4a, b, Daily body weight (a) or BAT temperature (b) of mice receiving i.c.v. BDNF as shown in Fig. 4a, b (n = 5 per group). c, Body weight of mice treated as shown in Fig. 4c, d (n = 5 per group). The multiple comparisons test was applied between Leptin and Leptin + K252 groups. d, e, ob/ob mice were given 14 days of leptin subcutaneously by osmotic pumps, or leptin together with twice daily i.p. injections of the TrkB antagonist ANA12, TH immunolabelling was visualized in iWAT (d) and BAT (e). Panels on right show quantification of images shown on left (n = 5 per group). f, Fluorescence microscopy showing immunolabelling of FOS in brain sections from 3-day leptin-treated ob/ob mice or PBS treated controls. Average number of neurons expressing FOS shown in bottom right corner of each panel (n = 4 per group). g, Immunostaining of PVH brain slices from LepR-Cre::LSL-tdTomato mice show a lack of cell bodies of LepR neurons in the PVH region; instead LepR neurons from outside of this region send dense projections to the PVH. h, Body weight progression of BDNFfl/fl mice treated as in Fig. 4i, j (n = 6 for AAV-GFP-Cre, n = 5 for AAV-GFP). i, Quantification of data shown in Fig. 4k, l reveals around 12% of POMC neurons were infected by Rabies and around 10% of Rabies infected cells in ARC were POMC+ (left panel, n = 2); around 5% of AGRP neurons were infected by Rabies and around 6% of Rabies infected cells in ARC were AGRP+ (right panel, n = 3). j, Scheme for ablating BDNF neurons in the PVH. AAV1-mCherry-flex-dtA virus was injected in the PVH of BDNF-IRES-cre::ob/ob to ablate BDNFPVH neurons or in Cre negative ob/ob littermates (as controls). k, 2 weeks post AAV1-mCherry-flex-dtA injection, mCherry transcripts (red) indicating neurons infected by the AAV, and BDNF transcripts (green) indicating BDNFPVH neurons, were visualized by FISH using RNAscope. l, Quantification of data shown in k. AAV1-mCherry-flex-dtA virus injection leads to a reduction in BDNF expressing cells in the PVH (n = 3 per group). m, Weekly body weight of BDNF-Cre::ob/ob or Cre negative ob/ob littermates post-injection of AAV1-mCherry-flex-dtA in the PVH but before leptin treatment (n = 5 for Cre-, n = 6 for Cre+). n, Daily body weight of BDNF-Cre::ob/ob or Cre negative ob/ob post leptin delivery (n = 5 for Cre-, n = 6 for Cre+). o, p, Daily food intake (o) or BAT temperature (p) from BDNF-Cre::ob/ob or Cre negative ob/ob littermates post leptin delivery. Daily food intake or BAT temperature of each mouse was the average of 4 consecutive days (n = 5 for Cre-, n = 6 for Cre+). Scale bars, 1 mm (d); 100 μm (eg, k). Data show mean ± SEM; significant differences between treatments calculated using two-way ANOVA followed by Bonferroni’s multiple comparisons test (ac, h, m, n), or Student’s two-tailed, unpaired t-test (all other panels). Source data

Extended Data Fig. 8 Scheme describing the leptin-dependent CNS–SNS feedback loop that regulates adipose tissue innervation.

Leptin from adipose tissue acts via a feedback loop starting with leptin responsive AGRP and POMC neurons in the ARC, and BDNF neurons in the PVH to modulate spinal preganglionic and sympathetic postganglionic neurons innervating adipose, to drive changes in levels of SNS innervation within fat.

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: 3-D reconstruction of Adipo-Clear processed iWAT from WT mice and ob/ob mice treated subcutaneously with either 14-day leptin or PBS control.

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Wang, P., Loh, K.H., Wu, M. et al. A leptin–BDNF pathway regulating sympathetic innervation of adipose tissue. Nature 583, 839–844 (2020). https://doi.org/10.1038/s41586-020-2527-y

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