CXCR3-expressing myeloid cells recruited to the hypothalamus protect against diet-induced body mass gain and metabolic dysfunction
Curation statements for this article:-
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eLife assessment
This work is of fundamental significance and has a compelling level of evidence for a new population that protects against obesity-induced hypothalamic inflammation. This topic will attract attention from a broad base of readers, from hypothalamic neuroscientists to immunologists with an interest in metabolism.
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Abstract
Microgliosis is an important component of diet-induced hypothalamic inflammation in obesity. A few hours after the introduction of a high-fat diet, the mediobasal hypothalamus resident microglia undergo morphological and functional changes toward an inflammatory phenotype. If the consumption of large amounts of dietary fats persists for long periods, bone marrow- derived myeloid cells are recruited and integrated into a new landscape of hypothalamic microglia. However, it is currently unknown what are the transcriptional signatures and specific functions exerted by either resident or recruited subsets of hypothalamic microglia. Here, the elucidation of the transcriptional signatures revealed that resident microglia undergo only minor changes in response to dietary fats; however, under the consumption of a high-fat diet, there are major transcriptional differences between resident and recruited microglia with a major impact on chemotaxis. In addition, in recruited microglia, there are major transcriptional differences between females and males with an important impact on transcripts involved in neurodegeneration and thermogenesis. The chemokine receptor CXCR3 emerged as one of the components of chemotaxis with the greatest difference between recruited and resident microglia, and thus, was elected for further intervention. The hypothalamic immunoneutralization of CXCL10, one of the ligands for CXCR3, resulted in increased body mass gain and reduced energy expenditure, particularly in females. Furthermore, the chemical inhibition of CXCR3 resulted in a much greater change in phenotype with increased body mass gain, reduced energy expenditure, increased blood leptin, glucose intolerance, and reduced insulin. Thus, this study has elucidated the transcriptional differences between resident and recruited hypothalamic microglia in diet-induced obesity, identifying chemokines as a relevant subset of genes undergoing regulation. In addition, we showed that a subset of recruited microglia expressing CXCR3 has a protective, rather than a detrimental role in the metabolic outcomes promoted by the consumption of a high-fat diet, thus, establishing a new concept in obesity-associated hypothalamic inflammation.
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eLife assessment
This work is of fundamental significance and has a compelling level of evidence for a new population that protects against obesity-induced hypothalamic inflammation. This topic will attract attention from a broad base of readers, from hypothalamic neuroscientists to immunologists with an interest in metabolism.
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Reviewer #1 (Public Review):
Summary:
The present work from Velloso and collaborators investigated the transcription profiles of resident and recruited hypothalamic microglia. They found sex-dependent differences between males and females and identified the protective role of chemokine receptor CXCR3 against diet-induced obesity.
Strengths:
(1) Novelty
(2) Relevance, since this work provides evidence about a subset of recruited microglia that has a protective effect against DIO. This provides a new concept in hypothalamic inflammation and obesity.Weaknesses:
(1) Lack of mechanistic insight into the sex-dependent effects.
(2) Analysis of indirect calorimetry data requires more depth.
(3) A deeper analysis of hypothalamic inflammation and ER stress pathways would strengthen the manuscript. -
Reviewer #2 (Public Review):
Summary:
This study by Mendes et al provides novel key insights into the role of chemotaxis and immune cell recruitment into the hypothalamus in the development of diet-induced obesity. Specifically, the authors reveal that although transcriptional changes in hypothalamic resident microglia following exposure to high-fat feeding are minor, there are compelling transcriptomic differences between resident microglia and microglia recruited to the hypothalamus, and these are sexually dimorphic. Using independent loss-of-function studies, the authors also demonstrate an important role of CXCR3 and hypothalamic CXCL10 in the hypothalamic recruitment of CCR2+ positive cells on metabolism following exposure to high-fat diet-feeding in mice. This manuscript puts forth conceptually novel evidence that inhibition of …
Reviewer #2 (Public Review):
Summary:
This study by Mendes et al provides novel key insights into the role of chemotaxis and immune cell recruitment into the hypothalamus in the development of diet-induced obesity. Specifically, the authors reveal that although transcriptional changes in hypothalamic resident microglia following exposure to high-fat feeding are minor, there are compelling transcriptomic differences between resident microglia and microglia recruited to the hypothalamus, and these are sexually dimorphic. Using independent loss-of-function studies, the authors also demonstrate an important role of CXCR3 and hypothalamic CXCL10 in the hypothalamic recruitment of CCR2+ positive cells on metabolism following exposure to high-fat diet-feeding in mice. This manuscript puts forth conceptually novel evidence that inhibition of chemotaxis-mediated immune cell recruitment accelerates body weight gain in high-fat diet-feeding, suggesting that a subset of microglia that express CXCR3 may confer protective, anti-obesogenic effects.
Strengths:
The work is exciting and relevant given the prevalence of obesity and the consequences of inflammation in the brain on perturbations of energy metabolism and ensuant metabolic diseases. Hypothalamic inflammation is associated with disrupted energy balance, and activated microglia within the hypothalamus resulting from excessive caloric intake and saturated fatty acids are often thought to be mediators of impairment of hypothalamic regulation of metabolism. The present work reports a novel notion in which immune cells recruited into the hypothalamus that express chemokine receptor CXCR3 may have a protective role against diet-induced obesity. In vivo studies reported herein demonstrate that inhibition of CXCR3 exacerbates high-fat diet-induced body weight gain, increases circulating triglycerides and fasting glucose levels, worsens glucose tolerance, and increases the expression of orexigenic neuropeptides, at least in female mice.
This work provides a highly interesting and needed overview of preclinical and clinical brain inflammation, which is relevant to readers with an interest in metabolism and immunometabolism in the context of obesity.
Using flow cytometry, cell sorting, and transcriptomics including RNA-sequencing, the manuscript provides novel insights into transcriptional landscapes of resident and recruited microglia in the hypothalamus. Importantly, sex differences are investigated.
Overall, the manuscript is perceived to be highly interesting, relevant, and timely. The discussion is thoughtful, well-articulated, and a pleasure to read and felt to be of interest to a broad audience.
Weaknesses:
There were no major weaknesses perceived. Some comments for potential textual additions to the results/discussion are listed in recommendations to authors.
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