Lipoprotein lipase maintains microglial innate immunity in obesity.
Open accessAbstract
Consumption of a hypercaloric diet upregulates microglial innate immune reactivity along with a higher expression of lipoprotein lipase (Lpl) within the reactive microglia in the mouse brain. Here, we show that knockdown of the Lpl gene specifically in microglia resulted in deficient microglial uptake of lipid, mitochondrial fuel utilization shifting to glutamine, and significantly decreased immune reactivity. Mice with knockdown of the Lpl gene in microglia gained more body weight than control mice on a high-carbohydrate high-fat (HCHF) diet. In these mice, microglial reactivity was significantly decreased in the mediobasal hypothalamus, accompanied by downregulation of phagocytic capacity and increased mitochondrial dysmorphologies. Furthermore, HCHF-diet-induced POMC neuronal loss was accelerated. These results show that LPL-governed microglial immunometabolism is essential to maintain microglial function upon exposure to an HCHF diet. In a hypercaloric environment, lack of such an adaptive immunometabolic response has detrimental effects on CNS regulation of energy metabolism.
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Both increased and decreased microglial inflammatory activity within the mediobasal hypothalamus can disrupt leptin/melanocortin related neuronal signaling, a pathway central to the regulation of energy balance.
“Recent studies have shown that both increased and decreased microglial inflammatory activity within the mediobasal hypothalamus can disrupt leptin/melanocortin related neuronal signaling, a pathway that is central to the regulation of energy balance (Gao et al., 2017; Valdearcos et al., 2017; Kim et al., 2019).”
From Deletion of the Alzheimer’s disease risk gene Abi3 locus results in obesity and systemic metabolic disruption in mice (2022) · cites this paper as Gao et al., 2017
The Results report reduced microglial reactivity alongside fewer POMC neurons in the mediobasal hypothalamus of high-carbohydrate, high-fat-diet-fed mice. The Discussion links POMC neurons to melanocortin signaling and energy expenditure, but says it is unclear whether increased microglial activation harms hypothalamic neurons. The paper does not establish disruption of leptin signaling. (LLM, conf=0.87)
Experimental — accuracy not yet measuredDeleting a gene specifically within microglia decreased the number of microglia within the mediobasal hypothalamus but exacerbated diet induced obesity.
“Conversely, a recent study demonstrated that by deleting a gene specifically within microglia, the number of microglia within the mediobasal hypothalamus decreased but diet induced obesity was exacerbated (Gao et al., 2017).”
From Deletion of the Alzheimer’s disease risk gene Abi3 locus results in obesity and systemic metabolic disruption in mice (2022) · cites this paper as Gao et al., 2017
Altered microglia function within the hypothalamus has been connected to the maintenance of body weight and obesity.
“Importantly, altered microglia function within the hypothalamus has been connected to the maintenance of body weight and obesity (Valdearcos et al., 2014, 2017; Andre et al., 2017; Dorfman et al., 2017; Gao et al., 2017; Rosin et al., 2018; De Luca et al., 2019; Kim et al., 2019; Campolim et al., 2020).”
From Deletion of the Alzheimer’s disease risk gene Abi3 locus results in obesity and systemic metabolic disruption in mice (2022) · cites this paper as Gao et al., 2017
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Self-citation
- Authors
- Gao, Y., Vidal-Itriago, A., Kalsbeek, M. J., Layritz, C., García-Cáceres, C., Tom, R. Z., Eichmann, T. O., Vaz, F. M., Houtkooper, R. H., van der Wel, N., Verhoeven, A. J., Yan, J., Kalsbeek, A., Eckel, R. H., Hofmann, S. M., & Yi, C.-X.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- Helmholtz Munich (DE)
- University of Graz (AT)
- Central South University (CN)
- Netherlands Institute for Neuroscience (NL)
- University of Colorado Anschutz (US)
- Corresponding author
- Yi, Chun-Xia
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 20
- Issue
- 13
- Pages
- 3034-3042
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2757631244
- Cited by
- 123
- References
- 34
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 20 · 2023: 13 · 2022: 23 · 2021: 20 · 2020: 7 · 2019: 10 · 2018: 10 · 2017: 1
- FWCI
- 3.82
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion, cc-by-nc-nd)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion, cc-by-nc-nd)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Site cant be reached (submittedVersion, cc-by-nc-nd)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- AMC
- Dutch Diabetes Fonds (2015.82.1826)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- lipoprotein lipase, microglia, innate immunity, obesity, hypercaloric diet, immunometabolism, glutamine metabolism, lipid uptake, phagocytosis, POMC neurons, hypothalamus, high-fat high-carbohydrate diet
- MeSH terms
- Animals, Immunity, Innate, Lipoprotein Lipase, Obesity, Microglia, Mice
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