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Astrocytic BDNF signaling within the ventromedial hypothalamus regulates energy homeostasis

Nature Metabolism volume 4, pages 627–643 (2022)Cite this article

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Abstract

Brain-derived neurotrophic factor (BDNF) is essential for maintaining energy and glucose balance within the central nervous system. Because the study of its metabolic actions has been limited to effects in neuronal cells, its role in other cell types within the brain remains poorly understood. Here we show that astrocytic BDNF signaling within the ventromedial hypothalamus (VMH) modulates neuronal activity in response to changes in energy status. This occurs via the truncated TrkB.T1 receptor. Accordingly, either fasting or central BDNF depletion enhances astrocytic synaptic glutamate clearance, thereby decreasing neuronal activity in mice. Notably, selective depletion of TrkB.T1 in VMH astrocytes blunts the effects of energy status on excitatory transmission, as well as on responses to leptin, glucose and lipids. These effects are driven by increased astrocytic invasion of excitatory synapses, enhanced glutamate reuptake and decreased neuronal activity. We thus identify BDNF/TrkB.T1 signaling in VMH astrocytes as an essential mechanism that participates in energy and glucose homeostasis.

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Fig. 1: VMH neuronal activity is dynamically regulated by energy status and BDNF signaling.
Fig. 2: Energy status and BDNF regulate astrocytic glutamate uptake at VMH synapses.
Fig. 3: TrkB.T1 signaling in VMH astrocytes is essential for the regulation of energy balance.
Fig. 4: Depletion of TrkB.T1 from VMH astrocytes of adult mice leads to impaired glycemic control and leptin resistance.
Fig. 5: Depletion of TrkB.T1 from VMH astrocytes of adult mice decreases neuronal activity.
Fig. 6: Specific depletion of TrkB.T1 from VMH astrocytes in adult mice leads to increased glutamate uptake at excitatory synapses.
Fig. 7: Knockdown of TrkB.T1 in VMH astrocytes increases astrocyte invasion of VMH synapses.

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All data associated with this study are presented in the paper or the extended data figures. Source data are provided with this paper.

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Acknowledgements

We thank B. Xu for the floxed TrkB animals and the Danbolt laboratory for the anti-GLAST antibody. We thank the HMS Electron Microscopy Facility and M. Ericsson for electron microscopy imaging, consultation and services. We thank the Vanderbilt Hormone Assay and Analytical Services Core and Lipid Core supported by NIH grants DK059637 and DK020593, specifically D. Edgerton, E. Allen and C. Harris for assisting in tissue and serum catecholamine and lipid analysis. We thank the Imaging, Genomics and Circuits Behavior Cores at the Tufts Center for Neuroscience Research. This work was supported by grants by the National Institute of Neurological Disorders and Stroke and the National Institute of Diabetes and Digestive and Kidney Diseases awarded to M.R. (1R21NS091871 and 1R01DK117935-01) and D.A. (1F31DK118789-01A1), the Synapse Neurobiology Training Program awarded to D.A. (5T32NS061764-09) and the Training Program in Nutrition, Obesity and Metabolic Disorders awarded to A.M. (T32DK124170).

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Authors and Affiliations

  1. Graduate Program in Neuroscience, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA, USA

    Dominique Ameroso, Stella Chen, Chris G. Dulla & Maribel Rios

  2. Graduate Program in Cell, Molecular and Developmental Biology, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA, USA

    Alice Meng, Chris G. Dulla & Maribel Rios

  3. Graduate Program in Biochemical and Molecular Nutrition, Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA

    Jennifer Felsted

  4. Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA

    Chris G. Dulla & Maribel Rios

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Contributions

D.A., M.R. and C.D. designed experiments. D.A., A.M., S.C. and J.F. conducted experiments. D.A., A.M. and M.R. analyzed and interpreted the results. D.A. and M.R. wrote the manuscript.

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Correspondence to Maribel Rios.

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Nature Metabolism thanks Michela Matteoli and the other, anonymous, reviewers for their contribution to the peer review of this work. Primary handling editors: Christoph Schmitt and Ashley Castellanos-Jankiewicz.

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Extended data

Extended Data Fig. 1 Intrinsic excitability of VMH neurons is not regulated by energy status or BDNF signaling.

a. Amplitude of sEPSCs in VMH neurons of fed (n = 21) and fasted WT (n = 21) and fed BDNF2L/2LCK:Cre mice (n = 19) (4–6 mice per group), Ordinary One-way ANOVA, p = 0.3. b. Amplitude of sEPSCs in VMH neurons of in WT Fed + aCSF (n = 13), Fasted + aCSF (n = 13) and Fasted + BDNF conditions (n = 12) (4 mice per group), Ordinary One-way ANOVA, p = 0.136. c. Input-output curves from VMH neurons in fed (n = 19) and fasted WT (n = 18) and fed BDNF2L/2LCK-Cre mice (n = 17) (3–4 mice per group). Two-way repeated measures ANOVA: Interaction, p = 0.7; Genotype, p = 0.3. d. Representative Traces showing resulting hyperpolarization or evoked action potentials in response to current injection steps of -120 mV and 120 mV. Data represented as mean + /- SEM.

Source data

Extended Data Fig. 2 Energy status and BDNF regulate astrocytic glutamate uptake at VMH synapses.

a. Representative traces of raw NMDAR responses (light purple), responses +100 uM DL-TBOA (dark purple) and responses + 50 uM APV (light gray). For following panels, WT Fed (n = 8), WT Fasted (n = 7) and Fed BDNF 2 L/2 L CK:Cre (n = 10). b. Amplitude (pA) of NMDAR responses before and after DL-TBOA application. c. Charge transfer (pA*ms) of NMDAR responses before and after DL-TBOA application. d. Decay (weighted tau) of NMDAR responses before and after DL-TBOA application. Two-way ANOVA: Genotype, p = 0.01; p = 0.0005; Interaction of genotype and DL-TBOA, p = 0.09. Bonferroni multiple comparisons, *, p = 0.001. Data represented as mean + /- SEM.

Source data

Extended Data Fig. 3 Energy status regulates astrocytic glutamate uptake at VMH synapses via BDNF signaling.

a. Representative traces of raw NMDAR responses (light purple), responses +100 uM DL-TBOA (dark purple) and responses + 50 uM APV (light gray). For following panels, Fed + aCSF (n = 6), Fasted + aCSF (n = 7), Fasted + BDNF (n = 6). b. Amplitude (pA) of NMDAR responses before and after DL-TBOA application. c. Charge transfer (pA*ms) of NMDAR responses before and after DL-TBOA application. d. Decay (weighted tau) of NMDAR responses before and after DL-TBOA application. Two-way ANOVA: Condition, p = 0.007; DL-TBOA, p = 0.02; Interaction of condition and DL-TBOA, p = 0.0009. Bonferroni multiple comparisons, *, p < 0.0001. Data represented as mean + /- SEM.

Source data

Extended Data Fig. 4 TrkB.T1 in VMH astrocytes is an essential regulator of body weight under standard chow conditions.

a. Expression of the neuronal marker b3 tubulin (FT n = 5, Astrocyte n = 7) and b. GLT-1 in mRNA isolated from VMH astrocytes and flowthrough (FT n = 3, Astrocyte n = 3). c. Immunolabeling of TrkB.T1 in the VMH of a TrkB F/F animal injected unilaterally with AAV5–GFAP-GFP–Cre 4 weeks post-surgery. Scale bar 15 uM. d. Colocalization of AAV5-GFAP-GFP–Cre with GFP signal with astrocytes (Sox9 + cells) and exclusion from neurons (NeuN + cells). Scale bar 50 uM. e. Colocalization of AAV5-GFAP-driven GFP signal with astrocytic (Sox9), neuronal (NeuN) and microglial (Iba)-specific markers. Scale bar 150 nM. f. Image showing that viral spread is limited to the VMH. g. Western blot and analysis showing TrkB.T1 expression in Control and TrkB.T1 KD mice within the VMH (n = 6) and the DMH of mice (n = 5). Data collected from one experiment. Student’s two-sided t-test, *, p = 0.01. Data represented as mean + /- SEM.

Source data

Extended Data Fig. 5 Depletion of TrkB.T1 from VMH astrocytes leads to increased body weight and alterations in locomotor activity, sympathetic tone and leptin insensitivity.

a. Body weights of TrkB.T1 KD (n = 10) and control males (n = 13). Two-way RM ANOVA: Genotype, p = 0.02; Time, p < 0.0001; Time x Genotype Interaction, p < 0.0001; Bonferroni multiple comparisons, *, p < 0.05. b. Body weights of TrkB.T1 KD (n = 11) and control females (n = 8). Two-way RM ANOVA: Genotype, p = 0.04; Time, p < 0.0001; Time x Genotype Interaction, p < 0.0001; Bonferroni multiple comparisons, *, p < 0.05, #, p = 0.09. c. Percentage body weight gain in TrkB.T1 KD (n = 7) and wild-type C57Bl6 males (n = 4) delivered AAV5-GFAP-GFP or AAV5-GFAP-GFP-Cre to the VMH. Two-way RM ANOVA: Genotype, p = 0.01; Bonferroni multiple comparisons, *, p < 0.5. d. Fine movements per hour of TrkB.T1 KD and control animals over 6 days (n = 7–9). Students two-sided t-test, *, p = 0.009. e – g. Norepinephrine levels in tissues from TrkB.T1 KD and control animals (n = 7). Student’s two-sided t-test, *, p = 0.01. h. Experimental design and daily weight change in TrkB.T1 KD and control male mice 4 weeks post-surgery in response to IP administration of vehicle for 3 days followed by administration of leptin (3 ug/g) for 3 days. Data are represented as mean + /- SEM.

Source data

Extended Data Fig. 6 The use of serotype AAV2 and a CMV promoter to knockdown TrkB is specific to neurons.

a. Diagram showing experimental approach for depleting TrkB from neurons bilaterally in the VMH of adult mice. b. Co-immunolabeling of VMH showing colocalization of AAV2-CMV-driven GFP signal with the neuronal marker NeuN but not with the astrocytic marker Sox9 or the microglial marker Iba1. Scale bar 50 nM. c. TrkB.T1 and TrkB.FL expression in floxed TrkB mice delivered AAV2-CMV-GFP (control) or AAV2-CMV-GFP–Cre (TrkB KD) to the VMH (n = 6). Student’s two-sided t-test, *, p = 0.01, **, p = 0.0016. Data represented as mean + /- SEM. d. Representative western blot showing viral knockdown of TrkB in VMH. Data collected from one experiment.

Source data

Extended Data Fig. 7 TrkB in VMH neurons is not required for the regulation of energy balance under chow conditions but is essential for glycemic control.

A. Percent body weight gain in Neuronal TrkB KD and control mice (n = 6). Two-way RM ANOVA: Genotype, p = 0.88; Time, p < 0.0001; Interaction, p = 0.85; Subjects (matching), p < 0.0001. B. Body weights of Neuronal TrkB KD and control mice (n = 7). Two-way RM ANOVA: Genotype, p = 0.44; Time, p < 0.0001; Interaction, p 0.76; Subjects (matching), p < 0.0001. C. Average weekly food intake weeks 3–6 post-surgery in neuronal TrkB KD (n = 8) and control (n = 6) mice. Student’s two-sided t-test, NS. D. Core body temperatures in neuronal TrkB KD (n = 8) and control (n = 6) mice. Student’s two-sided t-test, NS. E. Basic movements per hour of neuronal TrkB KD (n = 8) and control (n = 6) mice recorded over 6 days. F. Serum levels of leptin (pg/mL) in fed animals (n = 6). Students two-sided t-test, *, p = 0.02. G. Norepinephrine levels in indicated tissues in neuronal TrkB KD (n = 6) and control (n = 5) mice. Student’s two-sided t-test, *, p = 0.05. H. Glucose tolerance test of neuronal TrkB KD (n = 8) and control (n = 6) mice. Two-way RM ANOVA; Time, p < 0.0001; Genotype, p = 0.1; Interaction, p = 0.01. Bonferroni multiple comparisons, *, p = 0.04. I. GTT area under the curve. Students two-sided t-test, p = 0.08. J. Insulin tolerance test (n = 7). Two-way RM ANOVA; Time, p < 0.0001; Genotype, p = 0.65; Interaction, p = 0.48. Bonferroni multiple comparisons. K. ITT area under the curve. Students t-test, NS. Data represented as mean + /- SEM.

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Extended Data Fig. 8 Selective depletion of TrkB.T1 from VMH astrocytes in adult mice does not alter VMH neuronal excitatory synapse density.

a. Representative images of VMH co-immunolabeled with anti-PDS95 and anti-vGlut2. Arrows indicate PSD95 and vGlut2 colocalization (scale bar 15 uM). b. Density of excitatory synapses (colocalization of vGlut2 and PSD95) in the VMH of TrkB.T1 KD (n = 8) and control mice (n = 7). Students two-tailed t-test, NS. Data are represented as mean + /- SEM.

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Extended Data Fig. 9 Selective depletion of TrkB.T1 from VMH astrocytes in adult mice leads to increased glutamate uptake at synapses.

a. Representative traces of raw NMDAR responses (light purple), responses + 100 uM DL-TBOA (dark purple), and responses + 50 uM APV (light gray). For following panels, Control Fed (n = 9), Control Fasted (n = 7), TrkB.T1 Fed (n = 7), TrkB.T1 Fasted (n = 9). b. Amplitude (pA) of NMDAR responses before and after DL-TBOA application. c. Charge transfer (pA*ms) of NMDAR responses before and after DL-TBOA application. d. Decay (weighted tau) of NMDAR responses before and after DL-TBOA application. Two-way ANOVA: Genotype, p = 0.03; Treatment, p < 0.0001; Genotype x Treatment Interaction, p = 0.01. Bonferroni multiple comparisons, *, p = 0.02. **, p = 0.005, ***, p < 0.0001. Data represented as + /- SEM.

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Ameroso, D., Meng, A., Chen, S. et al. Astrocytic BDNF signaling within the ventromedial hypothalamus regulates energy homeostasis. Nat Metab 4, 627–643 (2022). https://doi.org/10.1038/s42255-022-00566-0

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