Obesity remodels activity and transcriptional state of a lateral hypothalamic brake on feeding

Rossi, Mark A.; Basiri, Marcus L.; McHenry, Jenna A.; Kosyk, Oksana; Otis, James M.; Munkhof, Hanna E. van den; Bryois, Julien; Hübel, Christopher; Breen, Gerome; Guo, Wilson; Bulik, Cynthia M.; Sullivan, Patrick F.; Stuber, Garret D.

doi:10.1126/science.aax1184

Cited by 131 publications

(142 citation statements)

References 43 publications

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“…Similar patterns of gene expression are observed in scRNA-Seq data obtained from Lhx6 neurons in the adult hypothalamus ( Fig. 18) (D. W. Mickelsen et al, 2019;Rossi et al, 2019). However, all these enriched markers (neuropeptides and neurotransmitters) are not specific to Lhx6 neurons but rather expressed broadly in hypothalamic GABAergic neurons ( Fig.…”

Section: Resultssupporting

confidence: 79%

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Gene regulatory networks controlling differentiation, survival, and diversification of hypothalamic Lhx6-expressing GABAergic neurons

Kim

Wang

et al. 2020

Preprint

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GABAergic neurons of the hypothalamus regulate many innate behaviours, but little is known about the mechanisms that control their development. We previously identified hypothalamic neurons that express the LIM homeodomain transcription factor Lhx6, a master regulator of cortical interneuron development, as sleep-promoting. In contrast to telencephalic interneurons, hypothalamic Lhx6 neurons do not undergo long-distance tangential migration, and do not express cortical interneuronal markers such as Pvalb. Here, we show that Lhx6 is necessary for survival of hypothalamic neurons, and that Dlx1/2, Nkx2-2, and Nkx2-1 are each required for specification of spatially distinct subsets of hypothalamic Lhx6 neurons. We identify a broad range of neuropeptides that are enriched in spatially segregated subsets of hypothalamic Lhx6 neurons, and distinct from those seen in cortical neurons. These findings identify common and divergent mechanisms by which Lhx6 controls the development of GABAergic neurons in the hypothalamus compared to telencephalic interneurons.

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Section: Resultssupporting

confidence: 79%

“…Differential peaks from ATAC-Seq between cortical and hypothalamic Lhx6-GFP + cells at P0. Mickelsen et al, 2019;Rossi et al, 2019).…”

Section: Statisticsmentioning

confidence: 99%

Gene regulatory networks controlling differentiation, survival, and diversification of hypothalamic Lhx6-expressing GABAergic neurons

Kim

Wang

et al. 2020

Preprint

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“…scRNAseq identifies transcriptionally distinct clusters among neuronal and non-neuronal cells. To characterize transcriptional identities of single cells in the mammalian habenula, we utilized droplet (Macosko et al, 2015;Rossi et al, 2019) based chromium technology developed by 10x Genomics (Zheng et al, 2017). We microdissected the habenula from brain live slices of adult male mice (P50-55), enzymatically digested the tissue to obtain well dissociated highly viable single cells (viability >80 %), captured single cell transcriptomes, and generated cDNA libraries for subsequent sequencing (Figure 1).…”

Section: Resultsmentioning

confidence: 99%

Transcriptional and Spatial Resolution of Cell Types in the Mammalian Habenula

Hashikawa

Basiri

et al. 2019

Preprint

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SummaryThe habenula complex is appreciated as a critical regulator of motivated and pathological behavioral states via its output to midbrain nuclei. Despite this, transcriptional definition of cell populations that comprise both the medial (MHb) and lateral habenular (LHb) subregions in mammals remain undefined. To resolve this, we performed single-cell transcriptional profiling and highly multiplexed in situ hybridization experiments of the mouse habenula complex in naïve mice and those exposed to an acute aversive stimulus. Transcriptionally distinct neuronal cell types identified within the MHb and LHb, were spatially defined, and differentially engaged by aversive stimuli. Cell types identified in mice, also displayed a high degree of transcriptional similarity to those previously described in zebrafish, highlighting the well conserved nature of habenular cell types across the phylum. These data identify key molecular targets within habenula cell types, and provide a critical resource for future studies.

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“…Dipatrizio and Piomelli (2015) reported that the ingestion of fat-rich foods initiates a cephalically-driven induction of endocannabinoid activity in the gut and maximizes food consumption [38]. Rossi et al (2019) reported that HFD weakened the activity of glutamatergic nerve cells in the lateral hypothalamus, which promoted overeating and obesity [39]. Furthermore, leptin resistance in obese individuals is a potential cause of eating disorders [40,41].…”

Section: Discussionmentioning

confidence: 99%

Combined Soluble Fiber-Mediated Intestinal Microbiota Improve Insulin Sensitivity of Obese Mice

Liu

Gao

et al. 2020

Nutrients

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Dietary fiber, an important regulator of intestinal microbiota, is a promising tool for preventing obesity and related metabolic disorders. However, the functional links between dietary fiber, intestinal microbiota, and obesity phenotype are still not fully understood. Combined soluble fiber (CSF) is a synthetic mixture of polysaccharides and displays high viscosity, water-binding capacity, swelling capacity, and fermentability. We found that supplementing high-fat diet (HFD) with 6% CSF significantly improved the insulin sensitivity of obese mice without affecting their body weight. Replacing the HFD with normal chow basal diet (NCD), the presence of CSF in the feed significantly enhanced satiety, decreased energy intake, promoted weight and fat loss, and augmented insulin sensitivity. CSF also improved the intestinal morphological integrity, attenuated systemic inflammation, promoted intestinal microbiota homeostasis, and stabilized the production of short-chain fatty acids (SCFAs) that was perturbed during HFD-induced obesity, and these stabilizing effects were more prominent when the basal diet was switched to NCD. The enrichment of bacteria of the S24-7 family and Allobaculum genus increased markedly in the intestine following 6% CSF supplementation- and correlated with decreased adiposity and insulin resistance. Five bacterial genera that were decreased by CSF, including Oscillospira, unclassified Lachonospitaceae, unclassified Clostridiales, unclassified Desulfovibrionaceae, and unclassified Ruminococcae, were subjected to co-occurrence network analysis and were positively correlated to adiposity and insulin resistance, indicating a key role in the microbial response to CSF. Thus, CSF has a potential to promote insulin sensitivity and even reduce obesity via beneficial regulation of the gut microecosystem.

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Obesity remodels activity and transcriptional state of a lateral hypothalamic brake on feeding

Cited by 131 publications

References 43 publications

Gene regulatory networks controlling differentiation, survival, and diversification of hypothalamic Lhx6-expressing GABAergic neurons

Gene regulatory networks controlling differentiation, survival, and diversification of hypothalamic Lhx6-expressing GABAergic neurons

Transcriptional and Spatial Resolution of Cell Types in the Mammalian Habenula

Combined Soluble Fiber-Mediated Intestinal Microbiota Improve Insulin Sensitivity of Obese Mice

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