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Distinct basal forebrain-originated neural circuits promote homoeostatic feeding and suppress hedonic feeding in male mice

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Abstract

Feeding behaviour is influenced by two primary factors: homoeostatic needs driven by hunger and hedonic desires for pleasure even in the absence of hunger. While efficient homoeostatic feeding is vital for survival, excessive hedonic feeding can lead to adverse consequences such as obesity and metabolic dysregulations. However, the neurobiological mechanisms that orchestrate homoeostatic versus hedonic food consumption remain largely unknown. Here we show that GABAergic proenkephalin (Penk) neurons in the diagonal band of Broca (DBB) of male mice respond to food presentation. We further demonstrate that a subset of DBBPenk neurons that project to the paraventricular nucleus of the hypothalamus are preferentially activated upon food presentation during fasting periods and transmit a positive valence to facilitate feeding. On the other hand, a separate subset of DBBPenk neurons that project to the lateral hypothalamus are preferentially activated when detecting a high-fat high-sugar (HFHS) diet and transmit a negative valence to inhibit food consumption. Notably, when given free choice of chow and HFHS diets, mice with the whole DBBPenk population ablated exhibit reduced consumption of chow but increased intake of the HFHS diet, resulting in accelerated development of obesity and metabolic disturbances. Together, we identify a molecularly defined neural population in male mice that is crucial for the maintenance of energy balance by facilitating homoeostatic feeding while suppressing hedonic overeating.

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Fig. 1: DBBPenk neurons are activated by food.
Fig. 2: PVH-projecting DBBPenk neurons are preferentially activated by homoeostatic needs.
Fig. 3: DBBPenk neurons project to the PVH to promote feeding.
Fig. 4: LH-projecting DBBPenk neurons are preferentially activated by hedonic demands.
Fig. 5: DBBPenk neurons project to the LH to inhibit feeding.

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Data availability

All data generated or analysed during this study are included in this published article. No third-party materials were included in this paper. Source data are provided with this paper.

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Acknowledgements

The investigators were supported by grants from the USDA/CRIS (51000-064-01S to Y.X. and 3092-51000-062-04(B)S to C.W.), Texas Children’s Research Scholar funds (ACCT 3410 to Y.H.), American Heart Association (23POST1030352 to Hailan Liu) and National Institutes of Health NIDDK (1R01DK138123 and 1R01DK138518 to Y.X. and 1F32DK134121-01A1 to K.M.C.).

Author information

Author notes

  1. These authors contributed equally: Yang He, Yong Xu.

Authors and Affiliations

  1. USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

    Hailan Liu, Jonathan C. Bean, Yongxiang Li, Meng Yu, Olivia Z. Ginnard, Kristine M. Conde, Mengjie Wang, Xing Fang, Hesong Liu, Longlong Tu, Na Yin, Junying Han, Yongjie Yang, Chunmei Wang & Yong Xu

  2. Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA

    Qingchun Tong

  3. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    Benjamin R. Arenkiel

  4. Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

    Yang He

  5. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    Yong Xu

  6. Department of Medicine, Baylor College of Medicine, Houston, TX, USA

    Yong Xu

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  1. Hailan Liu
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Contributions

Hailan Liu was involved in the experimental design and most of procedures, data acquisition and analyses, and wrote the manuscript. Y.H. conducted electrophysiological experiments and data analysis. J.C.B. performed PCA analysis on the GRIN lens data. Y.L., M.Y., O.Z.G., K.M.C., M.W., X.F., Hesong Liu, L.T., N.Y. and J.H. contributed to the generation of study mice and data discussion. Y.Y., Q.T., B.R.A. and C.W. were involved in study design and data discussion. Y.X. conceptualized and designed this study. Y.X. and Y.H. supervised this work, and as such, had full access to all the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis.

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Correspondence to Yang He or Yong Xu.

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Nature Metabolism thanks Yu Fu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Ashley Castellanos-Jankiewicz, in collaboration with the Nature Metabolism team.

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Extended data

Extended Data Fig. 1 DBBPenk neurons are activated by inaccessible food.

a-c. GCaMP6m signals in DBBPenk neurons of male mice in response to inaccessible chow (a) or HFHS (b) diet or non-food object (c) after an overnight fast (n = 6). Time 0 marks the moment when mice detect food or object. d. GCaMP6m signals in DBBPenk neurons of overnight fasted male mice when they are biting chow food. Time 0 marks the moment when mice start to bite food. e. A representative trace showing the response of DBBPenk neurons when mice are approaching or biting chow diet. f. GCaMP6m signals in DBBPenk neurons of sated male mice when they are biting HFHS food. Time 0 marks the moment when mice start to bite food. g. A representative trace showing the response of DBBPenk neurons when mice are approaching or biting HFHS diet. Data are expressed as mean ± SEM.

Source data

Extended Data Fig. 2 PCA classification of DBBPenk neurons.

The principal-component analysis classifies the responses of DBBPenk neurons into distinct reaction patterns.

Source data

Extended Data Fig. 3 DBBPenk neurons are activated by inaccessible food and tail suspension.

a. Traces showing the mean alterations in GCaMP6m fluorescence across 5 different types (left panel) and changes in calcium fluorescence of 65 neurons (right panel) from 6 food-deprived male mice in the presence of inaccessible chow diets. b. Bar graph showing the area under the curve for a. c. Traces showing the mean alterations in GCaMP6m fluorescence across 5 different types (left panel) and changes in calcium fluorescence of 65 neurons (right panel) from 6 food-deprived male mice in the presence of inaccessible HFHS diets. d. Bar graph showing the area under the curve for c. e. Traces showing the mean alterations in GCaMP6m fluorescence across 5 different types (left panel) and changes in calcium fluorescence of 65 neurons (right panel) from 6 food-deprived male mice in the presence of non-food object. f. Bar graph showing the area under the curve for e. g. Traces showing the mean alterations in GCaMP6m fluorescence across 5 different types (left panel) and changes in calcium fluorescence of 65 neurons (right panel) from 6 satiated male mice in the presence of inaccessible HFHS diet. h. Bar graph showing the area under the curve for g. i. Traces showing the mean alterations in GCaMP6m fluorescence across 5 different types (left panel) and changes in calcium fluorescence of 65 neurons (right paenl) from 6 satiated male mice in response to a 5 s tail suspension. Time 0 marks the start of food approaching for a, c, e, g or tail suspension for i. j. Bar graph showing the area under the curve for i. n = 20 for type 1, 13 for type 2, 16 for type 3, 5 for type 4, 11 for type 5 for b, d, f, h, j. The identical cell possesses the same ID to facilitate the comparison. Data are expressed as mean ± SEM or individual data points. One-way ANOVA with Sidak’s post hoc analysis (b, d, f, h, j).

Source data

Extended Data Fig. 4 DBBPenk neurons are exclusively GABAergic.

a. Representative immunofluorescence images showing the expression of tdTomato and ChAT in the DBB of 3 Penk-ires2-Cre/Rosa26-LSL-tdTomato mice. b. Representative RNAscope images showing Penk, Vgat and Vglut2 mRNA in the DBB of Penk-ires2-Cre/Rosa26-LSL-tdTomato mice. c. The number of Penk+, Vgat+, Vglut2+ cells in the DBB (n = 3). d. The percentage of Penk-expressing GABA neurons in the DBB. Data are expressed as mean ± SEM or individual data points.

Source data

Extended Data Fig. 5 Projections from DBBPenk neurons.

a. Scheme for Cre-dependent ChR2 injection into the DBB of Penk-ires2-Cre mice. b. Representative images showing ChR2 expression in the DBB and EYFP-labelled fibres in the PVH, LH, OB, SuM, hippocampus and DRN of 3 male Penk-ires2-Cre mice.

Extended Data Fig. 6 PVH-projecting DBBPenk neurons are activated by homoeostatic needs and stress.

a. The number of DBBPenk neurons that project to the PVH. b. mCherry and GFP-labelled cell bodies in the DBB. c. Quantification of mCherry+ and GFP+ cells in the DBB. d. Representative image showing GCaMP6m expression in PVH-projecting DBBPenk neurons for 3 mice. e-f. GCaMP6m signals in PVH-projecting DBBPenk neurons in overnight fasted male mice in response to inaccessible chow (e) or HFHS (f) diets (n = 6). g. GCaMP6m signals in PVH-projecting DBBPenk neurons in satiated male mice in response to inaccessible HFHS diet (n = 6). h. GCaMP6m signals in PVH-projecting DBBPenk neurons in overnight fasted male mice in response to non-food object (n = 6). i-j. GCaMP6m signals in PVH-projecting DBBPenk neurons in satiated male mice in response to a 5 s tail suspension (i) and TMT exposure (j, n = 5). Time 0 marks the start of item detection (e-h) or treatment (i-j). k-l. GCaMP6m signals in PVH-projecting DBBPenk neurons in overnight fasted male mice that were pretreated with HFD for 4 weeks in response to chow (k) or high-fat (l) diets (n = 5). Time 0 marks the moment when mice detect food. m. GCaMP6m signals in PVH-projecting DBBPenk neurons in satiated male mice treated with HFD for 4 weeks in response to a 5 s tail suspension (n = 5). Time 0 marks the start of tail suspension. n-o. Total travel distance (n) and number of entries into the light-paired chamber (o) in male control and ChR2 expressing mice at various conditions (n = 7 per group). p. Representative RNAscope images showing Penk mRNA in the DBB of wild-type and Penk-ires2-Cre mice that had received retrograde Cre-dependent Flp into the PVH and Flp-dependent DTA injection into the DBB. q. Quantification of Penk+ neurons in the DBB of wild-type (n = 3) and Penk-ires2-Cre (n = 3) mice. Data are expressed as mean ± SEM or individual data points. Two-tailed unpaired Student’s t test (q) or one-way ANOVA with Sidak’s post hoc analysis (n-o).

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Extended Data Fig. 7 LH-projecting DBBPenk neurons are activated by hedonic demands and stress.

a. The number of DBBPenk neurons that project to the LH. b. Representative image showing GCaMP6m expression in LH-projecting DBBPenk neurons. c-d. GCaMP6m signals in LH-projecting DBBPenk neurons in overnight fasted male mice in response to inaccessible chow (c) or HFHS (d) diets (n = 6). e. GCaMP6m signals in LH-projecting DBBPenk neurons in satiated male mice in response to inaccessible HFHS diet (n = 6). f. GCaMP6m signals in LH-projecting DBBPenk neurons in overnight fasted male mice in response to non-food object (n = 6). g-h. GCaMP6m signals in LH-projecting DBBPenk neurons in satiated male mice in response to high-fat diet containing either 30% (g) or 60% (h) fat content (n = 5). i. Area under curve for g and h. j-k. GCaMP6m signals in LH-projecting DBBPenk neurons in satiated male mice in response to a 5 s tail suspension (j) and TMT exposure (k, n = 5). Time 0 marks the start of item detection (e-h) or treatment (j-k). l-m. GCaMP6m signals in LH-projecting DBBPenk neurons in satiated (l) or fasted (m) male mice that were pretreated with HFD for 4 weeks in response to HFD (n = 5). Time 0 marks the moment when mice detect food. n. GCaMP6m signals in LH-projecting DBBPenk neurons in satiated male mice treated with HFD for 4 weeks in response to a 5 s tail suspension (n = 5). Time 0 marks the start of tail suspension. o-p. Total travel distance (o) and number of entries into the light-paired chamber (p) in male control and ChR2 expressing mice at various conditions (n = 7 per group). q. Representative RNAscope images showing Penk mRNA in the DBB of wild-type and Penk-ires2-Cre mice that had received retrograde Cre-dependent Flp into the LH and Flp-dependent DTA injection into the DBB. r. Quantification of Penk+ neurons in the DBB of wild-type (n = 3) and Penk-ires2-Cre (n = 3) mice. Data are expressed as mean ± SEM or individual data points. Two-tailed unpaired Student’s t test (i, r) or one-way ANOVA with Sidak’s post hoc analysis (o-p).

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Extended Data Fig. 8 DBBPenk neurons are required to maintain energy homoeostasis.

a. Scheme for Cre-dependent DTR delivery into the DBB of Penk-ires2-Cre mice. b. Representative RNAscope images showing Penk mRNA in the DBB of wild-type and Penk-ires2-Cre mice who had both received Cre-dependent AAV encoding DTR injection into the DBB followed by DT treatment. c. Quantification of Penk+ neurons in the DBB of wild-type (n = 5) and Penk-ires2-Cre (n = 6) mice receiving AAV-DIO-DTR injection into the DBB. d-e. Cumulative chow intake (d) and body weight change (e) after DT injection in male control (n = 8) and DTR expressed (n = 7) mice. f. Total travel distance, centre entries, and centre duration in the open field box test in male control (n = 8) and DTR expressed (n = 7) mice. g. Total travel distance and open arm entries in the elevated plus maze test in male control (n = 8) and DTR expressed (n = 7) mice. h. Open arm duration in the elevated plus maze test in male control (n = 8) and DTR expressed (n = 7) mice. i-l. Chow (i), HFHS (j) and calorie intake (k) and body weight change (l) in male control (n = 8) and DTR expressed (n = 7) mice after DT injection, mice were provided with free access to chow and HFHS diet. m. Blood glucose level in control (n = 8) and DTR expressing (n = 7) mice 3 weeks after DT injection. n. Glucose tolerance test in male control (n = 8) and DTR expressing (n = 7) mice 4 weeks after DT injection. o. Area under curve for n. p. Insulin sensitivity test in male control (n = 8) and DTR expressed (n = 7) mice 5 weeks after DT injection. q. Area under curve for p. Data are expressed as mean ± SEM or individual data points. Two-tailed unpaired Student’s t test (c, f-h, m, o, q) or two-way ANOVA with Sidak’s post hoc analysis (d-e, i-l, n, p). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

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Liu, H., Bean, J.C., Li, Y. et al. Distinct basal forebrain-originated neural circuits promote homoeostatic feeding and suppress hedonic feeding in male mice. Nat Metab (2024). https://doi.org/10.1038/s42255-024-01099-4

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