Deletion of the Alzheimer’s disease risk gene Abi3 locus results in obesity and systemic metabolic disruption in mice
Open accessAbstract
Alzheimer’s disease (AD) genetics studies have identified a coding variant within ABI3 gene that increases the risk of developing AD. Recently, we demonstrated that deletion of the Abi3 gene locus dramatically exacerbates AD neuropathology in a transgenic mouse model of amyloidosis. In the course of this AD project, we unexpectedly found that deletion of the Abi3 gene locus resulted in a dramatic obese phenotype in non-transgenic mice. Here, we report our investigation into this serendipitous metabolic finding. Specifically, we demonstrate that mice with deletion of the Abi3 gene locus (Abi3–/–) have dramatically increased body weight and body fat. Further, we determined that Abi3–/– mice have impaired energy expenditure. Additionally, we found that deletion of the Abi3 gene locus altered gene expression within the hypothalamus, particularly within immune-related pathways. Subsequent immunohistological analysis of the central nervous system (CNS) revealed that microglia number and area were decreased specifically within the mediobasal hypothalamus of Abi3–/– mice. Altogether, this investigation establishes the functional importance of the Abi3 gene locus in the regulation of systemic metabolism and maintenance of healthy body weight. While our previous findings indicated the importance of Abi3 in neurodegeneration, this study indicates that Abi3 related functions are also essential for metabolic regulation.
AI snapshot
Written from the paper’s full text.
TL;DR
Deletion of the Alzheimer’s disease risk gene locus Abi3 in non-transgenic mice produced an obese phenotype with increased body weight and fat mass, impaired glucose and insulin tolerance, and reduced light-cycle energy expenditure. The study also found weight-independent hypothalamic transcriptomic changes and decreased microglia number/area specifically in the mediobasal hypothalamus.
Key findings
- Abi3–/– mice weighed on average 10.70 g (32.4%) more than Abi3+/+ mice and had 7.11 g (208.4%) more fat mass; lean mass was not significantly altered.
- Abi3–/– mice showed impaired glucose tolerance and insulin sensitivity, with significantly elevated blood glucose during GTT at 60, 90, and 120 min and during ITT at 30, 45, and 60 min; plasma total cholesterol and leptin were also significantly elevated.
- Food intake and movement did not differ, but Abi3–/– mice had a significantly lower slope for energy expenditure vs. weight during the light cycle, indicating impaired energy expenditure.
- Hypothalamic RNA-seq identified 31 weight-covariate-controlled differentially expressed genes in Abi3–/– vs. Abi3+/+ mice, but no DEGs in brown adipose tissue; microglia number and area were decreased specifically in the mediobasal hypothalamus, not cortex, hippocampus, or whole hypothalamus.
Methods
- Non-transgenic male littermates from a 5XFAD × Abi3–/– cross were used at 15 months of age, with ad libitum food and water; body weight/composition, GTT, ITT, metabolic cage calorimetry, cholesterol assay, and leptin ELISA were performed.
- Bulk RNA-seq was performed on hypothalamus and brown adipose tissue from Abi3+/+ (n = 4) and Abi3–/– (n = 4) mice, with DESeq2 differential expression analysis using body weight as a covariate; DEGs were defined by Benjamini-Hochberg adjusted p ≤ 0.05.
- Iba1 immunofluorescence was quantified in coronal brain sections from Abi3+/+ (n = 5) and Abi3–/– (n = 5) mice across cortex, hippocampus, whole hypothalamus, and mediobasal hypothalamus; unpaired t-tests, two-way ANOVA with Tukey’s post-hoc, and simple linear regression were used.
Limitations
- The paper states that the obese phenotype was discovered unexpectedly in already aged 15-month-old mice, so it may be age dependent; only male mice were available because females were used for another project, leaving sex differences untested.
- The paper states that findings were observed in mice already obese, so additional mechanisms may drive the phenotype, and peripheral dysfunction could partly underlie it; future microglial-specific inducible Abi3 knockout is suggested to address this.
- Evident from the text: RNA-seq and immunofluorescence used small samples (n = 4 and n = 5 per genotype), and the study is largely correlational, without longitudinal or causal experiments to establish whether microglial changes directly cause the metabolic phenotype.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
32 of 44 cited sources checked · 18 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Elevated leptin and cholesterol levels are characteristic of obesity.
“Elevated leptin and cholesterol levels are characteristic of obesity, and therefore these results further demonstrate the extent of the obese phenotype observed in Abi3–/– mice (Klop et al., 2013; Obradovic et al., 2021).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites Klop et al., 2013 source
The Abstract associates obesity with high LDL cholesterol, although the Introduction qualifies typical LDL cholesterol as normal or only slightly increased. The Introduction mentions leptin as an adipokine but does not say its levels are elevated in obesity. Thus the cholesterol portion has qualified support; the elevated-leptin portion is not supported by this copy. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites Obradovic et al., 2021 source
The Introduction and “Leptin Expression in Obesity” section describe elevated leptin as a common characteristic of obesity. The Introduction lists dyslipidemia among obesity-associated conditions, but the paper does not specifically say that elevated cholesterol levels are characteristic of obesity. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Premisecitation
A rare coding variant within the ABI3 gene locus is associated with increased risk of Alzheimer's disease.
“Our initial interest in the ABI3 gene was inspired by a human genetics study that identified a rare coding variant within ABI3 gene locus that is associated with increased risk of AD (Sims et al., 2017).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Sims et al., 2017 source
- Premisecitation
Abi3 is predominantly expressed in myeloid derived monocytic and microglial immune cells.
“Abi3 is predominately expressed in myeloid derived monocytic and microglial immune cells (Zhang et al., 2014; Han et al., 2018).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites Zhang et al., 2014 source
The Abstract describes RNA-sequencing profiles of mouse cortical cell types, including microglia, but does not report Abi3 expression. Searches for “Abi3” and “Abelson interactor 3” found no passage establishing predominant expression in microglia or monocytic cells; the microglia-purification section instead discusses distinguishing microglia from contaminating peripheral macrophages. (LLM, conf=0.72)
Experimental — accuracy not yet measured - cites Han et al., 2018 source
- Interpretationreasoning
Abi3 may serve important roles at the intersection of metabolic, neurodegenerative, and immune regulation.
“In combination with our previous report demonstrating the importance of Abi3 in AD-like pathology (Karahan et al., 2021), we have provided evidence to suggest that Abi3 may serve important roles at the intersection of metabolic, neurodegenerative, and immune regulation.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Karahan et al., 2021 source
- Study design and conductcitation
The regression analysis addressed the potential confounding effects of differing body weight, thus isolating the direct effect of the deletion of Abi3 on energy expenditure.
“Critically, however, the regression analysis addressed the potential confounding effects of differing body weight (Tschöp et al., 2011), thus isolating the direct effect of the deletion of Abi3 on energy expenditure.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Tschöp et al., 2011 source
- Interpretationcitation
The obesity in Abi3-/- mice induced impairments to systemic glucose regulation, as is typically observed in obese mice.
“This likely suggests that the obesity in Abi3–/– mice induced impairments to systemic glucose regulation, as is typically observed in obese mice (King, 2012).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites King, 2012 source
- Findingown data
Abi3 genotype status had no impact on total or average movement counts.
“Abi3 genotype status had no impact on total or average movement counts (Supplementary Figure 2C).”
Quote in the paperNot a substantial claim - Findingown data
Within brown adipose tissue, no differentially expressed genes were identified between Abi3-/- and Abi3+/+ mice.
“Within the brown adipose tissue, no DEGs were identified between Abi3–/– vs. Abi3+/+ mice (Supplementary Figure 4).”
Quote in the paperSubstantial claim - Findingown data
Lean mass is not significantly altered in Abi3-/- mice compared to Abi3+/+ mice.
“Lean mass, however, was not significantly altered in Abi3–/– mice (Figure 1C).”
Quote in the paperNot a substantial claim - Findingown data
The DEGs were significantly enriched in pathways including G-protein/Rac1 signaling and leptin regulation.
“Further, these DEGs were significantly enriched in pathways including G-protein/Rac1 signaling and leptin regulation, among others (Figure 3C).”
Quote in the paperNot a substantial claim - Findingown data
There was no significant difference in Iba1+ cell number or area when evaluating the entire hypothalamus.
“Further, there was no significant difference in Iba1+ cell number or area when evaluating the entire hypothalamus (Figures 4E, F).”
Quote in the paperSubstantial claim - Findingown data
Abi3-/- mice weigh on average 10.70 g, or 32.4%, more than Abi3+/+ mice.
“Deletion of the Abi3 gene locus significantly increased body weight, with Abi3–/– mice weighing an average of 10.70 g, or 32.4%, more than Abi3+/+ mice (Figure 1A).”
Quote in the paperSubstantial claim - Findingown data
Abi3-/- mice have significantly elevated leptin concentration in plasma.
“Then, we performed a leptin ELISA on the plasma from these mice and similarly observed that Abi3–/– mice had significantly elevated leptin concentration (Supplementary Figure 3).”
Quote in the paperSubstantial claim - Findingown data
No differences in respiratory exchange ratio were observed between Abi3+/+ and Abi3-/- mice.
“Additionally, no differences in respiratory exchange ratio, a measure of carbohydrate vs. lipid fuel utilization, were observed between the Abi3+/+ and Abi3–/– mice (Supplementary Figure 1B).”
Quote in the paperNot a substantial claim - Findingown data
Abi3-/- mice have significantly elevated cholesterol levels in plasma.
“Using a colorimetric total cholesterol assay, we found that Abi3–/– mice had significantly elevated cholesterol levels (Supplementary Figure 3).”
Quote in the paperSubstantial claim - Findingown data
Abi3-/- mice have a significantly lower slope of energy expenditure versus weight during the light cycle than Abi3+/+ mice.
“However, further regression analysis comparing the relationship of energy expenditure vs. weight revealed that Abi3–/– mice had significantly lower slope than Abi3+/+ mice during the light cycle, indicative of impaired energy expenditure (Figure 2E).”
Quote in the paperSubstantial claim - Findingown data
Deletion of the Abi3 gene locus results in an obese phenotype in non-transgenic mice.
“In the course of this AD project, we unexpectedly found that deletion of the Abi3 gene locus resulted in a dramatic obese phenotype in non-transgenic mice.”
- Also stated in: § 3.1 Increase in body weight and fat mass and impairment of glucose and insulin tolerance in Abi3–/– mice · plain
“In the course of our AD project, we unexpectedly found that deletion of the Abi3 gene locus resulted in a dramatic obese phenotype in non-transgenic mice.”
- Also stated in: § 1 Introduction · plain
“we unexpectedly discovered that Abi3 knock-out (Abi3–/–) mice had an obese phenotype.”
Quote in the paperSubstantial claim - Also stated in: § 3.1 Increase in body weight and fat mass and impairment of glucose and insulin tolerance in Abi3–/– mice · plain
- Findingown data
Within the mediobasal subregion of the hypothalamus, Abi3-/- mice showed significantly lower number and area of Iba1+ cells.
“However, within the mediobasal subregion of the hypothalamus, a region critical to the regulation of energy balance, Abi3–/– mice showed significantly lower number and area of Iba1+ cells (Figures 4G, H).”
- Also stated in: § Abstract · plain
“Subsequent immunohistological analysis of the central nervous system (CNS) revealed that microglia number and area were decreased specifically within the mediobasal hypothalamus of Abi3–/– mice.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Findingown data
Abi3-/- mice exhibit impaired glucose tolerance relative to Abi3+/+ mice.
“These data indicate that Abi3–/– mice had impaired glucose tolerance relative to control.”
Quote in the paperSubstantial claim - Findingown data
Total number or area of Iba1+ cells were not altered in the cortex or hippocampus of Abi3-/- mice.
“The total number or area of Iba1+ cells were not altered in the cortex or hippocampus of Abi3–/– mice (Figures 4A–D).”
Quote in the paperSubstantial claim - Findingown data
No significant differences in slope of energy expenditure versus weight were detected between Abi3-/- and Abi3+/+ mice for the dark cycle or full day.
“No significant differences in slope were detected between Abi3–/– and Abi3+/+ mice for the dark cycle or full day regression analyses (Figures 2F, G).”
Quote in the paperNot a substantial claim - Findingown data
Within the hypothalamus, 31 weight covariate controlled differentially expressed genes were identified between Abi3-/- and Abi3+/+ mice, including Shank1 and Cartpt.
“Within the hypothalamus, however, 31 weight covariate controlled DEGs were identified, including Shank1 and Cartpt (Figure 3A).”
Quote in the paperSubstantial claim - Findingown data
The DEGs identified in Abi3-/- mice hypothalamus were significantly enriched in biologic processes including cytoskeletal regulation, synaptic cellular adhesion, and neuropeptide signaling.
“The DEGs identified in Abi3–/– mice were significantly enriched in biologic processes including cytoskeletal regulation, synaptic cellular adhesion, and neuropeptide signaling, among others (Figure 3B).”
Quote in the paperNot a substantial claim - Findingown data
Deletion of the Abi3 gene locus does not alter food intake in mice.
“The deletion of Abi3 gene locus did not alter food intake between groups (Figures 2A, B).”
Quote in the paperSubstantial claim - Findingown data
Abi3-/- mice have more fat mass than Abi3+/+ mice by an average of 7.11 g, or 208.4%.
“Specifically, Abi3–/– mice had more fat mass than Abi3+/+ mice by an average of 7.11 g, or 208.4% (Figure 1B).”
Quote in the paperSubstantial claim - Findingown data
Deletion of the Abi3 gene locus altered gene expression within the hypothalamus, particularly within immune-related pathways.
“Additionally, we found that deletion of the Abi3 gene locus altered gene expression within the hypothalamus, particularly within immune-related pathways.”
Quote in the paperNot a substantial claim - Findingown data
Hypothalamic DEGs were enriched in biologic processes including cellular adhesion at the synapse, energy balance related neuropeptide signaling (Cartpt) and cytoskeletal remodeling (Shank1).
“Furthermore, our pathway analysis indicated that the hypothalamic DEGs were enriched in biologic processes including cellular adhesion at the synapse, energy balance related neuropeptide signaling (Cartpt) and cytoskeletal remodeling (Shank1).”
Quote in the paperSubstantial claim - Findingown data
In 15-month-old male Abi3-/- mice, body weight and fat mass were significantly increased compared to Abi3+/+ mice.
“In these mice, we found that body weight and fat mass were significantly increased in Abi3–/– mice”
Quote in the paperSubstantial claim - Findingown data
In these 15-month-old male mice, lean mass was not altered between Abi3-/- and Abi3+/+ mice.
“while lean mass was not altered”
Quote in the paperSubstantial claim - Interpretationreasoning
The change in microglia number could indicate that the loss of Abi3 might induce obesity through altered microglia function within the mediobasal hypothalamus.
“Therefore, the change in microglia number could indicate that the loss of Abi3 might induce obesity through altered microglia function within the mediobasal hypothalamus.”
Quote in the paperSubstantial claim- Rests on an assumption: The mediobasal hypothalamus is central to the regulation of systemic metabolism, and microglia play a key role in that regulation.
- Rests on an assumption: Iba1+ cell number and area reflect microglia function.
- Interpretationown data
Abi3-/- mice have impaired energy expenditure during the light cycle.
“Further, we determined that Abi3–/– mice have impaired energy expenditure.”
- Also stated in: § 3.2 Energy expenditure during light cycle is impaired, while food intake is unchanged, in Abi3–/– mice · hedged
“However, further regression analysis comparing the relationship of energy expenditure vs. weight revealed that Abi3–/– mice had significantly lower slope than Abi3+/+ mice during the light cycle, indicative of impaired energy expenditure (Figure 2E).”
Quote in the paperSubstantial claim - Also stated in: § 3.2 Energy expenditure during light cycle is impaired, while food intake is unchanged, in Abi3–/– mice · hedged
- Interpretationreasoning
The elevated leptin and cholesterol results further demonstrate the extent of the obese phenotype observed in Abi3-/- mice.
“Elevated leptin and cholesterol levels are characteristic of obesity, and therefore these results further demonstrate the extent of the obese phenotype observed in Abi3–/– mice (Klop et al., 2013; Obradovic et al., 2021).”
Quote in the paperNot a substantial claim - Interpretationown data
Abi3 related functions are also essential for metabolic regulation.
“While our previous findings indicated the importance of Abi3 in neurodegeneration, this study indicates that Abi3 related functions are also essential for metabolic regulation.”
Quote in the paperSubstantial claim - Interpretationown data
This study is the first to determine the functional importance of the Abi3 gene locus in the regulation of systemic metabolism and maintenance of healthy weight.
“Altogether, this study is the first to determine the functional importance of the Abi3 gene locus in the regulation of systemic metabolism and maintenance of healthy weight.”
Quote in the paperSubstantial claim - Interpretationcitation
An appropriate level of microglia activity within the hypothalamus is necessary to maintain proper control of energy balance.
“Our data contribute to the growing concept that an appropriate level of microglia activity within the hypothalamus is necessary to maintain proper control of energy balance (Valdearcos et al., 2019).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Valdearcos et al., 2019 source
- Study design and conductown data
The RNA-seq differential expression analysis controlled for body weight as a covariate to isolate changes due to absence of Abi3 rather than secondary to body weight differences.
“To isolate changes that were due to the absence of Abi3 itself, rather than secondary to Abi3 dependent differences in body weight, we performed weight-covariate controlled analysis of the RNA-seq data.”
Quote in the paperSubstantial claim - Interpretationown data
The deletion of Abi3 is impacting the function of microglia within the hypothalamus.
“As Abi3 is predominantly expressed by microglia within the CNS, our transcriptomic analyses suggests that the deletion of Abi3 is impacting the function of microglia within the hypothalamus.”
Quote in the paperSubstantial claim- Rests on an assumption: Abi3 is predominantly expressed by microglia within the CNS.
- Interpretationown data
The hypothalamus, not BAT, triggered the initial dysfunction that subsequently drives the impairment to energy expenditure.
“This could suggest that hypothalamus, not BAT, triggered the initial dysfunction that subsequently drives the impairment to energy expenditure.”
Quote in the paperSubstantial claim - Study design and conductnone given
The findings were observed in mice that were already obese.
“It is important, however, to note that these findings were observed in mice that were already obese.”
Quote in the paperSubstantial claim - Study design and conductnone given
The original observation of the obese phenotype did not occur until the mice were 15 months old.
“our original observation of the obese phenotype did not occur until the mice were 15 months old.”
Quote in the paperNot a substantial claim - Interpretationown data
Loss of ABI3 function may drive obesity through impairments to energy expenditure.
“Overall, these findings suggest that the loss of ABI3 function may drive obesity through impairments to energy expenditure.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 18
- May combine two claims. 18
Classified as probably not a substantial claim.
PremisecitationMicroglia within the hypothalamus affect the progression and onset of obesity.
“recent studies have demonstrated that microglia, in particular microglia within the hypothalamus, affects the progression and onset of obesity (Coats et al., 2017; Valdearcos et al., 2017, 2019; Hill et al., 2018).”
Quote in the paperSubstantial claim2 of 3 sources checked- cites Coats et al., 2017 source
The Introduction and Results discuss macrophages in adipose tissue during diet-induced obesity, not microglia in the hypothalamus. Searches for hypothalamic microglia and their role in obesity onset or progression found no passage in our copy addressing that claim; the Discussion’s mention of brain injury does not establish it. (LLM, conf=0.74)
Experimental — accuracy not yet measured - cites Valdearcos et al., 2017, 2019
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Hill et al., 2018 source
The Abstract and Discussion discuss macrophage populations in adipose tissue, not microglia in the hypothalamus. Searches for hypothalamic microglia and obesity onset or progression found no passage in our copy addressing that claim; the paper’s adipose-tissue findings do not establish it. (LLM, conf=0.76)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationDeletion of the Abi3 gene locus significantly exacerbated Aβ pathology and neuroinflammation in 5xFAD mice.
“We recently reported that deletion of the Abi3 gene locus significantly exacerbated Aβ pathology and neuroinflammation in these mice (Karahan et al., 2021).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Karahan et al., 2021 source
Classified as probably not a substantial claim.
PremisecitationDisrupted immune function is a potential link between metabolic and neurodegenerative disease states.
“Intriguingly, it has been suggested that disrupted immune function is a potential link between these disease states (Pugazhenthi et al., 2017; Newcombe et al., 2018).”
Quote in the paperSubstantial claim2 of 2 sources checkedClassified as probably not a substantial claim.
PremisecitationPerturbations in immune function exacerbate neurodegeneration and metabolic diseases.
“Perturbations in immune function have been demonstrated to exacerbate neurodegeneration and metabolic diseases (Lumeng and Saltiel, 2011; Ransohoff, 2016; Reilly and Saltiel, 2017).”
Quote in the paperSubstantial claim1 of 3 sources checked- cites Lumeng and Saltiel, 2011 source
The nature of obesity-induced inflammation (page unavailable) links inflammatory immune responses to metabolic dysfunction, and the Conclusion describes inflammation worsening insulin resistance and diabetes progression. The paper discusses brain inflammation in relation to metabolic function, but the passages do not show that immune perturbations exacerbate neurodegeneration; its mention of neuronal injury describes injury inducing inflammation instead. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites Ransohoff, 2016 source
- cites Reilly and Saltiel, 2017
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAbi3 is suggested to exert its function through participation in the WAVE2 complex, a regulator of cytoskeletal remodeling.
“While much remains to be discovered regarding the cellular functions of Abi3, it is suggested to exert its function through its participation in the WASP family verprolin-homologous protein-2 (WAVE2) complex, a regulator of cytoskeletal remodeling (Takenawa and Suetsugu, 2007; Moraes et al., 2017).”
Quote in the paperNot a substantial claim1 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationDeleting 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).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Gao et al., 2017 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationGenetic or pharmacologic treatments that increase microgliosis within the mediobasal hypothalamus are capable of inducing obesity even in the absence of dietary challenge.
“It has also been reported that genetic or pharmacologic treatments that increase microgliosis within the mediobasal hypothalamus are capable of inducing obesity even in the absence of dietary challenge (Valdearcos et al., 2017; Campolim et al., 2020).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites Valdearcos et al., 2017 source
The Abstract (page not provided) reports that genetic activation of microglia caused MBH microgliosis and weight gain in mice without a dietary challenge. It does not support the pharmacologic part: the pharmacologic treatment described in the Abstract and Results depleted microglia and reduced weight gain rather than inducing obesity. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites Campolim et al., 2020 source
The Discussion (page unavailable) reports increased hypothalamic Iba1, a marker of microglial activation, after five days of PM2.5 exposure; the Results report obesity after 12 weeks, and the Methods specify standard chow. This supports microglial activation and subsequent obesity without a high-fat diet, but the intervention was air-pollution exposure—not a genetic or pharmacologic treatment that increased microgliosis—and the paper does not establish that microgliosis itself induced obesity. (LLM, conf=0.86)
Experimental — accuracy not yet measured
May combine two claims.
InterpretationcitationDeletion of Abi3 gene locus can have dramatic impacts on the seemingly distinct disease states of obesity and neurodegeneration, likely due to disruptions in microglia functions.
“our study has now demonstrated how deletion of Abi3 gene locus can have dramatic impacts on the seemingly distinct disease states of obesity and neurodegeneration, likely due to disruptions in microglia functions (Karahan et al., 2021).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Karahan et al., 2021 source
The Introduction and Discussion report that deleting the Abi3 locus worsened Alzheimer’s-related pathology in 5XFAD mice and altered microglial functions. The paper does not report an effect on obesity, so it supports the neurodegeneration-related part of the cited claim but not the asserted impact on both disease states. Page numbers were not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim. May combine two claims.
PremisecitationEnergy expenditure in mice is predominantly regulated by the hypothalamus, centrally, and largely by thermogenic brown adipose tissue (BAT), peripherally.
“Energy expenditure in mice is predominantly regulated by the hypothalamus, centrally, and largely by thermogenic brown adipose tissue (BAT), peripherally (Varela and Horvath, 2012; Harms and Seale, 2013; Schneeberger et al., 2014).”
Quote in the paperSubstantial claim2 of 3 sources checked- cites Varela and Horvath, 2012 source
The Introduction (page unavailable) describes the hypothalamus as pivotal in regulating energy homeostasis, supporting the central-regulation part of the claim. It does not establish that the hypothalamus predominantly regulates energy expenditure in mice or that thermogenic brown adipose tissue accounts for much of its peripheral regulation; searches for brown adipose tissue and thermogenesis found no supporting passage. (LLM, conf=0.83)
Experimental — accuracy not yet measured - cites Harms and Seale, 2013
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Schneeberger et al., 2014 source
The ARC neuronal circuits section reports that hypothalamic neurons increase BAT thermogenic function and affect energy expenditure in mice. But the paper does not establish that the hypothalamus is the predominant central regulator or that BAT accounts for most peripheral energy expenditure; its Concluding remarks describe regulation by multiple circuits, including the brainstem. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured
May combine two claims.
Interpretationown dataThe functions of ABI3 are important not only in response to neurodegenerative pathology but also in the regulation of systemic metabolism.
“Altogether, our data suggest that the functions of ABI3 are not only important in the response to neurodegenerative pathology (Karahan et al., 2021) but also in the regulation of systemic metabolism.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Karahan et al., 2021 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationBoth 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).”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites Gao et al., 2017 source
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 measured - cites Valdearcos et al., 2017 source
The Results section (‘Microglial A20 Deletion Induces Diet-Independent Metabolic Dysfunction’; page not provided) reports that increased microglial inflammatory activation reduced leptin-induced signaling in mediobasal hypothalamic neurons. The Introduction (page not provided) says that restraining microglial inflammatory activity protected mice from diet-induced hyperphagia and obesity. The paper does not show that decreased activity disrupts leptin or melanocortin neuronal signaling. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites Kim et al., 2019 source
The Discussion links high-fat-diet-induced microglial activation and inflammatory signaling to hypothalamic metabolic dysfunction. But the Results section on POMC neuronal activation reports that mice lacking microglial UCP2 had greater POMC activation and retained leptin responsiveness under high-fat feeding. The paper therefore supports disruption associated with increased microglial activity, not the claim that decreased activity also disrupts this signaling. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationReducing dietary induced microgliosis can mitigate weight gain.
“Further, it has been demonstrated that reducing this dietary induced microgliosis can mitigate weight gain (Andre et al., 2017; Valdearcos et al., 2017; Kim et al., 2019).”
Quote in the paperNot a substantial claim3 of 3 sources checkedClassified as probably not a substantial claim.
PremisecitationMultiple studies have demonstrated that microglia number increases within the mediobasal hypothalamus during diet induced obesity.
“Multiple studies have demonstrated that microglia number increases within the mediobasal hypothalamus during diet induced obesity (Thaler et al., 2012; de Kloet et al., 2014; Valdearcos et al., 2014; Schur et al., 2015; Waise et al., 2015; Baufeld et al., 2016; Guillemot-Legris et al., 2016).”
Quote in the paperSubstantial claim3 of 3 sources checkedClassified as probably not a substantial claim.
PremisecitationAltered 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).”
Quote in the paperSubstantial claim2 of 3 sources checkedMay combine two claims.
Findingown dataAbi3-/- mice exhibit insulin resistance or impaired insulin response relative to Abi3+/+ mice.
“In the ITT, Abi3–/– mice had significantly elevated blood glucose levels at 30, 45, and 60 min, indicative of insulin resistance, as compared to Abi3+/+ mice (Figure 1F).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIba1+ cell size was increased only in the hippocampus, but not other brain regions, of Abi3-/- mice.
“Iba1+ cell size was increased only in the hippocampus, but not other brain regions of Abi3–/– mice (Supplementary Figure 5).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataMicroglia number and area were decreased specifically within the mediobasal hypothalamus, but not in other areas, of Abi3-/- mice compared to Abi3+/+.
“FIGURE 4 Deletion of Abi3 gene locus reduces microglia number and area within the mediobasal hypothalamus, but not other brain regions.”
- Also stated in: § 4 Discussion · plain
“Intriguingly, we found that microglia number and area were decreased specifically within the mediobasal hypothalamus, but not in other areas, of Abi3–/– mice compared to Abi3+/+.”
Quote in the paperSubstantial claim- Also stated in: § 4 Discussion · plain
May combine two claims.
Findingown dataA weight-covariate controlled bulk RNA-seq analysis did not identify any DEGs within BAT but did identify DEGs within the hypothalamus.
“This approach did not identify any DEGs within the BAT but did identify DEGs within the hypothalamus.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAbi3-/- mice had significantly reduced slope on the regression of energy expenditure vs. body weight during the light cycle but not the dark cycle.
“However, Abi3–/– mice had significantly reduced slope on the regression of energy expenditure vs. body weight during the light cycle but not the dark cycle.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAbi3-/- mice had impairments in both glucose tolerance and insulin sensitivity.
“Furthermore, we found that Abi3–/– mice had impairments in both glucose tolerance and insulin sensitivity.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataFood intake and overall movement did not change between Abi3-/- and Abi3+/+ mice.
“The food intake and the overall movement of the mice did not change between the genotypes.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThis investigation establishes the functional importance of the Abi3 gene locus in the regulation of systemic metabolism and maintenance of healthy body weight.
“Altogether, this investigation establishes the functional importance of the Abi3 gene locus in the regulation of systemic metabolism and maintenance of healthy body weight.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationMetabolic diseases such as obesity increase the risk of developing neurodegenerative disease such as Alzheimer's disease.
“Additionally, it has been reported that metabolic diseases, such as obesity, increase the risk of developing neurodegenerative disease such as Alzheimer’s disease (AD) (Mazon et al., 2017; Zhuang et al., 2021).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
InterpretationcitationBoth hyperreactivity and reduced reactivity of hypothalamic microglia may lead to dysfunctional regulation of systemic metabolism.
“It appears that both hyperreactivity and the reduced reactivity of hypothalamic microglia may lead to dysfunctional regulation of systemic metabolism.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe study was performed in accordance with an approved animal protocol from the Institutional Animal Care and Use Committee of Indiana University School of Medicine.
“The present study was performed in accordance with our reviewed and approved animal protocol from the Institutional Animal Care and Use Committee of Indiana University School of Medicine.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenOnly male mice were available for this investigation because female mice were already used for another project.
“Additionally, only male mice were available for this investigation because female mice were already used for another project.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenDifferentially expressed genes were defined by an FDR-adjusted (Benjamini-Hochberg) p-value ≤ 0.05.
“Differential expressed genes were considered to be genes with an FDR-adjusted (Benjamini-Hochberg) p-value ≤ 0.05.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductown dataThe study used non-transgenic littermates from a cross between 5XFAD and Abi3-/- mice.
“The mice utilized in this study were initially generated from a cross between 5XFAD and Abi3–/– mice; our study utilized the non-transgenic littermates from this cross.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe increased body weight in Abi3-/- mice was driven predominantly by increased fat mass, which is indicative of an obese phenotype.
“These findings indicated that the increased weight was driven predominantly by increased fat mass, which is indicative of an obese phenotype.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe deletion of Abi3 gene locus itself, as opposed to Abi3 dependent differences in body weight, induced changes to gene expression within the hypothalamus but not within BAT.
“This suggests that the deletion of Abi3 gene locus itself, as opposed to Abi3 dependent differences in body weight, induced changes to gene expression within the hypothalamus but not within BAT.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataAbi3 is involved in both immune and metabolic regulation.
“In this report, we describe how an unexpected discovery revealed that an AD-related gene, Abelson interactor family member 3 (Abi3), is involved in both immune and metabolic regulation.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationMicroglia are highly dynamic cells that constantly survey their microenvironment and communicate with other CNS cells, both of which require cytoskeletal remodeling.
“Further, microglia are highly dynamic cells that are constantly surveying their microenvironment and communicating with other CNS cells, both of which are functions that require cytoskeletal remodeling (Uhlemann et al., 2016; Prinz et al., 2019).”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe animal study was reviewed and approved by the IUPUI Animal Care and Use Committee Indiana University School of Medicine at Indianapolis.
“The animal study was reviewed and approved by the IUPUI Animal Care and Use Committee Indiana University School of Medicine at Indianapolis.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
The role of Abi3 in the context of metabolic regulation and metabolic disease is completely unknown.
“However, the role of Abi3 in the context of metabolic regulation and metabolic disease is completely unknown.”
The paper relies on this without support.
The field currently has limited knowledge regarding the specific molecular drivers that alter the immune system to jointly modulate metabolic and neurodegenerative disease states.
“However, the field currently has limited knowledge regarding the specific molecular drivers that alter the immune system to jointly modulate metabolic and neurodegenerative disease states.”
The paper relies on this without support.
The mediobasal hypothalamus is central to the regulation of systemic metabolism, and microglia play a key role in that regulation.
“The mediobasal hypothalamus is an area that is central to the regulation of systemic metabolism, and it is postulated that microglia play a key role in that regulation.”
The paper relies on this without support.
Iba1+ cell number and area reflect microglia function.
“Therefore, the change in microglia number could indicate that the loss of Abi3 might induce obesity through altered microglia function within the mediobasal hypothalamus.”
The paper relies on this without support.
Abi3 is predominantly expressed by microglia within the CNS.
“As Abi3 is predominantly expressed by microglia within the CNS”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Abi3 knockout also increases body and fat mass and reduces energy expenditure.
“In addition, Abi3 KO also increases body and fat mass and reduces energy expenditure166.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [166]
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Thaler, J. P., Yi, C.-X., Schur, E. A., Guyenet, S. J., Hwang, B. H., Dietrich, M. O., Zhao, X., Sarruf, D. A., Izgur, V., Maravilla, K. R., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci59660 · Cited by 1,857 · cited 1× · see citing works
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BackgroundMicroglia in neurodegeneration
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BackgroundDyslipidemia in obesity: Mechanisms and potential targets
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ResultMapping the Mouse Cell Atlas by Microwell-Seq
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BackgroundMicroglia Biology: One Century of Evolving Concepts
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BackgroundThe use of animal models in diabetes research
King, A. J. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2012.01911.x · Cited by 1,303 · cited 1× · see citing works
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BackgroundAdapting to obesity with adipose tissue inflammation
Reilly, S. M., & Saltiel, A. R. (2017) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2017.90 · Cited by 1,204 · cited 1× · see citing works
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BackgroundARUK Consortium, Sims, R., GERAD/PERADES, C., van der Lee, S. J., Naj, A. C., Bellenguez, C., Badarinarayan, N., Jakobsdottir, J., Kunkle, B. W., Boland, A., et al. (2017) · Nature Genetics · doi:10.1038/ng.3916 · Cited by 1,126 · cited 1× · see citing works
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BackgroundInfluentialLeptin and Obesity: Role and clinical implication.
Obradovic, M., Sudar-Milovanovic, E., Soskic, S., Essack, M., Arya, S., Stewart, A. J., Gojobori, T., & Isenovic, E. R. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.585887 · Cited by 1,121 · cited 1× · see citing works
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ResultThe WASP-WAVE protein network: Connecting the membrane to the cytoskeleton.
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“While much remains to be discovered regarding the cellular functions of Abi3, it is suggested to exert its function through its participation in the WASP family verprolin-homologous protein-2 (WAVE2) complex, a regulator of cytoskeletal remodeling (Takenawa and Suetsugu, 2007; Moraes et al., 2017).”
BackgroundA guide to analysis of mouse energy metabolism
Tschöp, M. H., Speakman, J. R., Arch, J. R. S., Auwerx, J., Brüning, J. C., Chan, L., Eckel, R. H., Farese, R. V., Galgani, J. E., Hambly, C., et al. (2012) · Nature Methods · doi:10.1038/nmeth.1806 · Cited by 813 · cited 1× · see citing works
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BackgroundCommon neurodegenerative pathways in obesity, diabetes, and Alzheimer's disease
Pugazhenthi, S., Qin, L., & Reddy, P. H. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2016.04.017 · Cited by 697 · cited 1× · see citing works
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“Multiple studies have demonstrated that microglia number increases within the mediobasal hypothalamus during diet induced obesity (Thaler et al., 2012; de Kloet et al., 2014; Valdearcos et al., 2014; Schur et al., 2015; Waise et al., 2015; Baufeld et al., 2016; GuillemotLegris et al., 2016).”
BackgroundInflammation: the link between comorbidities, genetics, and Alzheimer’s disease
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“Intriguingly, it has been suggested that disrupted immune function is a potential link between these disease states (Pugazhenthi et al., 2017; Newcombe et al., 2018).”
BackgroundValdearcos, M., Douglass, J. D., Robblee, M. M., Dorfman, M. D., Stifler, D. R., Bennett, M. L., Gerritse, I., Fasnacht, R., Barres, B. A., Thaler, J. P., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.05.015 · Cited by 477 · cited 4× · see citing works
“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).”
BackgroundMethodInfluentialHorváth, T. L., Sármán, B., García‐Cáceres, C., Enriori, P. J., Sótonyi, P., Shanabrough, M., Borók, E., Argente, J., Chowen, J. A., Pérez–Tilve, D., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1004282107 · Cited by 446 · cited 1× · see citing works
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BackgroundVarela, L., & Horvath, T. L. (2012) · The EMBO Reports · doi:10.1038/embor.2012.174 · Cited by 426 · cited 1× · see citing works
“Energy expenditure in mice is predominantly regulated by the hypothalamus, centrally, and largely by thermogenic brown adipose tissue (BAT), peripherally (Varela and Horvath, 2012; Harms and Seale, 2013; Schneeberger et al., 2014).”
BackgroundDistinct macrophage populations direct inflammatory versus physiological changes in adipose tissue
Hill, D. A., Lim, H.-W., Kim, Y. H., Ho, W. Y., Foong, Y. H., Nelson, V. L., Nguyen, H. C. B., Chegireddy, K., Kim, J., Habertheuer, A., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1802611115 · Cited by 415 · cited 1× · see citing works
“This is relevant in the context of metabolism because recent studies have demonstrated that microglia, in particular microglia within the hypothalamus, affects the progression and onset of obesity (Coats et al., 2017; Valdearcos et al., 2017, 2019; Hill et al., 2018).”
BackgroundSelf-citationHypothalamic and brainstem neuronal circuits controlling homeostatic energy balance.
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“Energy expenditure in mice is predominantly regulated by the hypothalamus, centrally, and largely by thermogenic brown adipose tissue (BAT), peripherally (Varela and Horvath, 2012; Harms and Seale, 2013; Schneeberger et al., 2014).”
BackgroundCoats, B. R., Schoenfelt, K. Q., Barbosa-Lorenzi, V. C., Peris, E., Cui, C., Hoffman, A., Zhou, G., Fernandez, S., Zhai, L., Hall, B. A., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.08.096 · Cited by 291 · cited 1× · see citing works
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BackgroundMicroglial UCP2 mediates inflammation and obesity induced by high-fat feeding
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“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).”
BackgroundInfluentialHigh-fat diet-induced brain region-specific phenotypic spectrum of CNS resident microglia
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“Multiple studies have demonstrated that microglia number increases within the mediobasal hypothalamus during diet induced obesity (Thaler et al., 2012; de Kloet et al., 2014; Valdearcos et al., 2014; Schur et al., 2015; Waise et al., 2015; Baufeld et al., 2016; GuillemotLegris et al., 2016).”
BackgroundThe impact of obesity on neurodegenerative diseases.
Mazon, J. N., de Mello, A. H., Ferreira, G. K., & Rezin, G. T. (2017) · Life Sciences · doi:10.1016/j.lfs.2017.06.002 · Cited by 185 · cited 1× · see citing works
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BackgroundInhibiting microglia expansion prevents diet-induced hypothalamic and peripheral inflammation
André, C., Guzman-Quevedo, O., Rey, C., Rémus-Borel, J., Clark, S., Castellanos-Jankiewicz, A., Ladeveze, E., Leste-Lasserre, T., Nadjar, A., Abrous, D. N., et al. (2017) · Diabetes · doi:10.2337/db16-0586 · Cited by 182 · cited 2× · see citing works
“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).”
BackgroundSex differences in microglial CX3CR1 signalling determine obesity susceptibility in mice
Dorfman, M. D., Krull, J. E., Douglass, J. D., Fasnacht, R. D., Lara-Lince, F., Meek, T. H., Shi, X., Damian, V. M., Hồng, N. T., Matsen, M. E., et al. (2017) · Nature Communications · doi:10.1038/ncomms14556 · Cited by 169 · cited 1× · see citing works
“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).”
BackgroundGuillemot‐Legris, O., Masquelier, J., Everard, A., Cani, P. D., Alhouayek, M., & Muccioli, G. G. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0666-8 · Cited by 168 · see citing works
Schur, E. A., Melhorn, S. J., Oh, S.-K., Lacy, J. M., Berkseth, K. E., Guyenet, S. J., Sonnen, J. A., Tyagi, V., Leon, M. R. B. D., Leon, B. D., et al. (2015) · Obesity · doi:10.1002/oby.21248 · Cited by 152 · cited 1× · see citing works
“Multiple studies have demonstrated that microglia number increases within the mediobasal hypothalamus during diet induced obesity (Thaler et al., 2012; de Kloet et al., 2014; Valdearcos et al., 2014; Schur et al., 2015; Waise et al., 2015; Baufeld et al., 2016; GuillemotLegris et al., 2016).”
BackgroundOne-day high-fat diet induces inflammation in the nodose ganglion and hypothalamus of mice
Waise, T. M. Z., Toshinai, K., Naznin, F., NamKoong, C., Moin, A. S. M., Sakoda, H., & Nakazato, M. (2015) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2015.07.097 · Cited by 134 · cited 1× · see citing works
“Multiple studies have demonstrated that microglia number increases within the mediobasal hypothalamus during diet induced obesity (Thaler et al., 2012; de Kloet et al., 2014; Valdearcos et al., 2014; Schur et al., 2015; Waise et al., 2015; Baufeld et al., 2016; GuillemotLegris et al., 2016).”
BackgroundLipoprotein lipase maintains microglial innate immunity in obesity.
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., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.09.008 · Cited by 123 · cited 3× · see citing works
“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).”
BackgroundRosin, J. M., Vora, S. R., & Kurrasch, D. M. (2018) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2018.07.023 · Cited by 110 · see citing works
Campolim, C. M., Weissmann, L., Ferreira, C. K. D. O., Zordão, O. P., Dornellas, A. P. S., de Castro, G., Zanotto, T. M., Boico, V. F., Quaresma, P. G. F., Lima, R. P. A., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-67040-3 · Cited by 76 · cited 2× · see citing works
“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).”
Backgroundde Kloet, A. D., Pioquinto, D. J., Nguyen, D., Wang, L., Smith, J. A., Hiller, H., & Sumners, C. (2014) · Physiology & Behavior · doi:10.1016/j.physbeh.2014.01.016 · Cited by 66 · see citing works
Actin dynamics shape microglia effector functions.
Uhlemann, R., Gertz, K., Boehmerle, W., Schwarz, T., Nolte, C., Freyer, D., Kettenmann, H., Endres, M., & Kronenberg, G. (2016) · Brain Structure and Function · doi:10.1007/s00429-015-1067-y · Cited by 61 · cited 1× · see citing works
“Further, microglia are highly dynamic cells that are constantly surveying their microenvironment and communicating with other CNS cells, both of which are functions that require cytoskeletal remodeling (Uhlemann et al., 2016; Prinz et al., 2019).”
BackgroundLuca, S. N. D., Sominsky, L., Soch, A., Wang, H., Ziko, I., Rank, M. M., & Spencer, S. J. (2018) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2018.12.008 · Cited by 61 · see citing works
Karahan, H., Smith, D. C., Kim, B., Dabin, L. C., Al-Amin, M. M., Wijeratne, H. R. S., Pennington, T., Viana di Prisco, G., McCord, B., Lin, P. B.-C., et al. (2021) · Science Advances · doi:10.1126/sciadv.abe3954 · Cited by 53 · cited 8× · see citing works
“We recently reported that deletion of the Abi3 gene locus significantly exacerbated Aβ pathology and neuroinflammation in these mice (Karahan et al., 2021).”
BackgroundMethodInfluentialSelf-citationHypothalamic microglia as potential regulators of metabolic physiology.
Valdearcos, M., Myers, M. G., & Koliwad, S. K. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0040-0 · Cited by 52 · cited 2× · see citing works
“In the context of this study, it is possible that the deletion of the Abi3 gene locus impaired the ability of microglia to perform the complex functions that are necessary to regulate energy balance (Valdearcos et al., 2019; De Luca et al., 2020).”
BackgroundThe NESH/Abi-3-based WAVE2 complex is functionally distinct from the Abi-1-based WAVE2 complex
Sekino, S., Kashiwagi, Y., Kanazawa, H., Takada, K., Baba, T., Sato, S., Inoue, H., Kojima, M., & Tani, K. (2015) · Cell Communication and Signaling · doi:10.1186/s12964-015-0119-5 · Cited by 43 · cited 2× · see citing works
“be participant in cellular processes that require remodeling of the actin cytoskeleton, including cellular migration and membrane protrusion (Sekino et al., 2015; Karahan et al., 2021).”
BackgroundAssociations between obesity and Alzheimer’s disease: Multiple bioinformatic analyses.
Zhuang, Q.-S., Meng, L., Wang, Z., Shen, L., & Ji, H.-F. (2021) · Journal of Alzheimer's Disease · doi:10.3233/jad-201235 · Cited by 31 · cited 1× · see citing works
“Additionally, it has been reported that metabolic diseases, such as obesity, increase the risk of developing neurodegenerative disease such as Alzheimer’s disease (AD) (Mazon et al., 2017; Zhuang et al., 2021).”
BackgroundMicroglial regulation of satiety and cognition
Luca, S. N. D., Miller, A. A., Sominsky, L., & Spencer, S. J. (2020) · Journal of Neuroendocrinology · doi:10.1111/jne.12838 · Cited by 27 · see citing works
ABI3, a component of the WAVE2 complex, is potentially regulated by PI3K/AKT pathway
Moraes, L., Zanchin, N. I. T., & Cerutti, J. M. (2017) · Oncotarget · doi:10.18632/oncotarget.18840 · Cited by 22 · cited 1× · see citing works
“While much remains to be discovered regarding the cellular functions of Abi3, it is suggested to exert its function through its participation in the WASP family verprolin-homologous protein-2 (WAVE2) complex, a regulator of cytoskeletal remodeling (Takenawa and Suetsugu, 2007; Moraes et al., 2017).”
BackgroundMetabolic factors in the regulation of hypothalamic innate immune responses in obesity
Folick, A., Cheang, R. T., Valdearcos, M., & Koliwad, S. K. (2022) · Experimental & Molecular Medicine · doi:10.1038/s12276-021-00666-z · Cited by 22 · cited 1× · see citing works
“It has been postulated that microglia regulate control of energy balance via the modulation of neuronal signaling within the hypothalamus through microglia-neuron interactions (Folick et al., 2022).”
Background
Flagged first, then by citations
Cited by
Sorted by citations
He, C., Chen, B., Yang, H., & Zhou, X. (2025) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2025.1554398 · Cited by 38 · see citing works
Towards a Unitary Hypothesis of Alzheimer’s Disease Pathogenesis
Area-Gómez, E., & Schon, E. (2024) · Journal of Alzheimer's Disease · doi:10.3233/jad-231318 · Cited by 16 · see citing works
The WAVE complex in developmental and adulthood brain disorders
Kim, H.-G., Berdasco, C., Nairn, A. C., & Kim, Y. (2025) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01386-w · Cited by 8 · see citing works
Vastrad, B. M., Pattanashetti, S., & Vastrad, C. M. (2025) · Research Square · doi:10.21203/rs.3.rs-7522725/v1 · Cited by 4 · see citing works
Hussain, Z., & Nabeel, T. (2023) · Qlantic journal of social sciences. · doi:10.55737/qjss.766231428 · Cited by 1 · see citing works
Vastrad, B. M., & Vastrad, C. M. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.04.16.537071 · Cited by 1 · see citing works
Vastrad, B. M., & Vastrad, C. M. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.02.10.579759 · Cited by 1 · see citing works
Li, S., Lu, J., Zeng, K., Lu, X., Zhang, J., Feng, S., Liang, C., Cai, Y., Yao, S., Huang, Q., et al. (2026) · Alzheimer's & Dementia · doi:10.1002/alz.71812
“19 Recent studies have found that the ABI3 S209F variant is associated with an increased risk and earlier onset of AD, and when combined with apolipoprotein E ( APOE ) ε 4, it can promote region ‑ specific A β accumulationandmicroglialactivation.”
- Authors
- Smith, D. C., Karahan, H., Wijeratne, H. R. S., Al-Amin, M., McCord, B., Moon, Y., & Kim, J.
- Affiliations
- Indiana University Indianapolis (US)
- Indiana University School of Medicine
- Corresponding author
- Kim, Jungsu
- Venue
- Frontiers in Aging Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2022-12-22
- Volume
- 14
- Pages
- 1035572-1035572
- ISSN
- 1663-4365 (ISSN-L)
- PMC
- PMC9813750
- OpenAlex
- W4312187432
- Cited by
- 8
- References
- 49
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 2
- FWCI
- 0.72
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Aging Neuroscience (publishedVersion, cc-by)
- PubMed (publishedVersion)
- IUScholarWorks (Indiana University) (submittedVersion, cc-by)
- PubMed Central (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute on Aging (R01AG071281, RF1AG074543, R21AG072738)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK064466-20, DK097512)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- ABI3, gene deletion, obesity, body weight, energy expenditure, hypothalamus, microglia, mediobasal hypothalamus, immune gene expression, systemic metabolism, fat mass
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-17.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-17.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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