IDOL regulates systemic energy balance through control of neuronal VLDLR expression

IDOL controls the abundance of LDLR, VLDLR, and ApoER2 via ubiquitination, which targets the proteins for lysosomal degradation.

“IDOL controls the abundance of three proteins (LDLR, VLDLR, and ApoER2) via ubiquitination, which targets the proteins for lysosomal degradation9,13.”

• cites [9] Hong, C. et al. The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2. J. Biol. Chem. 285, 19720–19726 (2010). sourceSupported
• cites [13] Calkin, A. C. et al. FERM-dependent E3 ligase recognition is a conserved mechanism for targeted degradation of lipoprotein receptors. Proc. Natl Acad. Sci. USA 108, 20107–20112 (2011). sourceNot checked — no full text of the source

VLDLR-KO mice exhibited a reduction in mass and BMI relative to WT controls on a mixed background.

“One of the initial observations made by Herz and colleagues when they developed the VLDLR-KO mice was that the mice exhibited a reduction in mass and BMI relative to WT controls on a mixed background27.”

• cites [27] Frykman, P. K., Brown, M. S., Yamamoto, T., Goldstein, J. L. & Herz, J. Normal plasma lipoproteins and fertility in gene-targeted mice homozygous for a disruption in the gene encoding very low density lipoprotein receptor. Proc. Natl Acad. Sci. USA 92, 8453–8457 (1995). sourcePartly supported

  The Abstract reports that the authors produced VLDLR-knockout mice and detected a modest decrease in body weight and body mass index. Our copy does not specify a mixed genetic background or explicitly identify wild-type controls for that comparison. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

The viral-Cre approach used here suffers from the inherent weakness that the SynI promoter-driven Cre will be expressed in all infected neurons, which might affect the role of specific neuronal populations.

“We acknowledge that the viral-Cre approach used here suffers from the inherent weakness that the SynI promoter-driven Cre will be expressed in all infected neurons, which might might the role of specific neuronal populations51.”

• cites [51] Mancini, G. & Horvath, T. L. Viral vectors for studying brain mechanisms that control energy homeostasis. Cell Metab. 27, 1168–1175 (2018). sourceCould not verify

  The supplied passage has no section or page label and contains only reference links, not discussion of the viral-Cre approach. Searches for SynI, promoter-driven Cre expression, and neuronal specificity found no substantive passage in our copy that addresses the claim. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

Whole-body deletion of VLDLR is protective against diet-induced obesity.

“Whole body deletion of VLDLR has previously been shown to be protective against diet-induced obesity22,27,28.”

• cites [22] Goudriaan, J. R. et al. The VLDL receptor plays a major role in chylomicron metabolism by enhancing LPL-mediated triglyceride hydrolysis. J. Lipid Res. 45, 1475–1481 (2004). sourceSupported
• cites [27] Frykman, P. K., Brown, M. S., Yamamoto, T., Goldstein, J. L. & Herz, J. Normal plasma lipoproteins and fertility in gene-targeted mice homozygous for a disruption in the gene encoding very low density lipoprotein receptor. Proc. Natl Acad. Sci. USA 92, 8453–8457 (1995). sourcePartly supported

  The Abstract reports that mice lacking VLDL receptors had modestly lower body weight, body mass index, and adipose tissue mass. It mentions high-fat feeding but does not report that deletion specifically protected against diet-induced obesity, so the diet-specific claim goes beyond the passage. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [28] Goudriaan, J. R. et al. Protection from obesity in mice lacking the VLDL receptor. Arterioscler. Thromb. Vasc. Biol. 21, 1488–1493 (2001). sourceNot checked — no full text of the source

18-month-old chow-fed IDOL-KO mice are protected against age-induced obesity even on standard chow diet.

“18-month old chow-fed IDOL-KO mice (developed at UCLA) demonstrated that deletion of IDOL protected against age-induced obesity, even when the mice were fed standard chow diet”

Hepatic deletion of IDOL had no effect on glucose metabolism.

“nor on glucose metabolism (Extended Data Fig 2A, 2B), suggesting that the liver is not the primary driver of the global IDOL-KO phenotype.”

Loss of IDOL in mice protects against the development of diet-induced obesity and metabolic dysfunction.

“Here we show that loss of IDOL in mice protects against the development of diet-induced obesity and metabolic dysfunction by altering food intake and thermogenesis.”

Intestine-specific IDOL knockout did not affect glucose or insulin tolerance.

“and did not affect glucose or insulin tolerance (Extended Data Fig. 2G, 2H).”

Viral-Cre-mediated deletion of IDOL in neurons in the arcuate nucleus, ventromedial hypothalamus, or paraventricular nucleus of the hypothalamus was not sufficient to recapitulate the CreSynI Idolf/f mouse phenotype.

“viral-Cre-mediated deletion of IDOL in neurons in the arcuate nucleus (ARC), ventromedial hypothalamus (VMH), or the paraventricular nucleus of the hypothalamus (PVH) was not sufficient to recapitulate the CreSynIIdolf/f mouse phenotype”

Adipose-specific deletion of IDOL had no effect on glucose or insulin tolerance.

“or on glucose or insulin tolerance (Extended Data Fig. 2C, 2D).”

The ASO findings were confirmed in a second cohort of mice using a CNS-optimized negative control ASO.

“These findings were confirmed in a second cohort of mice using a CNS-optimized negative control ASO”

No statistically significant differences in energy expenditure were detected between CreSynI Idolf/f and Idolf/f littermates by indirect calorimetry.

“We assessed energy expenditure by indirect calorimetry but did not detect any statistically significant differences between the two groups.”

Adipose-specific transgenic IDOL mice are not protected from diet-induced obesity.

“Adipose-specific transgenic IDOL mice are not protected from diet-induced obesity.”

Single-cell RNA sequencing of the hypothalamus demonstrated that IDOL deletion altered gene expression linked to control of metabolism.

“Single-cell RNA sequencing of the hypothalamus demonstrated that IDOL deletion altered gene expression linked to control of metabolism.”

Vldlr is only appreciably expressed in neuron and oligodendrocyte cell populations in the hypothalamus.

“Vldlr is only appreciably expressed in neuron and oligodendrocyte cell populations.”

Reduced food intake in IDOL-KO mice was associated with reduced diet-induced adipose expansion.

“associated with reduced diet-induced adipose expansion (Fig 1G, 1H).”

Reduced adiposity in WD-fed IDOL-KO mice was associated with improved glucose clearance and insulin tolerance.

“The reduced adiposity in the WD-fed IDOL-KO mice was associated with improved glucose clearance (Fig. 1D; nine weeks of diet) and insulin tolerance (Fig. 1E; fourteen weeks of diet).”

Acute knockdown of Idol in the central nervous system increases energy expenditure.

“Acute knockdown of Idol in the central nervous system increases energy expenditure.”

IDOL-KO mice on western diet were leaner, averaging 11% body fat compared to 32% in WT mice.

“Body composition analysis by MRI revealed that IDOL-KO mice were leaner, averaging 11% body fat compared to 32% in the WT mice”

Male IDOL knockout mice have unchanged lean body mass across test diets despite adiposity changes measured by MRI.

“Unchanged lean body mass in male IDOL knockout mice administered test diets despite adiposity changes measured by MRI.”

Clustering analysis revealed several populations of neurons with incompletely overlapping clusters of wild-type and IDOL knockout cells, indicating altered global transcriptional profiles in these populations.

“the clustering analysis revealed several populations of neurons that had incompletely overlapping clusters of wild-type and IDOL knockout cells (Fig. 5C). Such separations indicate altered global transcriptional profiles in these populations.”

Global IDOL-KO mice housed at thermoneutrality gained less mass and adiposity on the obesogenic HFHC diet relative to WT mice.

“Relative to WT mice, global IDOL-KO mice gained less mass and adiposity on the obesogenic HFHC diet”

Muscle-specific IDOL knockout failed to recapitulate the effects of whole-body IDOL loss.

“Again, the tissue-selective knockout failed to recapitulate the effects of whole-body IDOL loss (Fig. 2E, 2J and Extended Data Fig. 2I, 2J).”

The increased energy expenditure in ASO-treated mice could not be explained by changes in locomotor activity.

“The increased energy expenditure could not be explained by changes in locomotor activity (Fig. 4G, 4H).”

Endothelial-specific IDOL knockout had no difference in glucose or insulin tolerance.

“There was also no difference in glucose or insulin tolerance between groups (Extended Data Fig. 2E, 2F).”

Loss of IDOL altered the expression of a battery of genes linked to energy balance in AGRP neurons.

“Analysis of transcript abundance in the AGRP neurons revealed that loss of IDOL altered the expression of a battery of genes linked to energy balance.”

LDLR is not required for IDOL's effects on the response to high-fat diet.

“Furthermore, the only lipoprotein receptor target of IDOL that is expressed by the liver is the LDL receptor, which we unequivocally demonstrated was not required for IDOL’s effects on the response to high-fat diet (Fig. 3A, 3B).”

CreR26/IDOL(AZ) mice maintained on low-fat low-cholesterol diet showed a lean phenotype after 20 weeks of age.

“When maintained on low-fat low-cholesterol diet (LFD), these CreR26/IDOL(AZ) mice also showed a lean phenotype after 20-weeks of age”

Group-housed IDOL-deficient knockout mice fed a western diet for 15 weeks were 22% lighter than WT controls.

“Group-housed IDOL-deficient knockout mice fed a western diet (WD) enriched in fat and cholesterol for 15 weeks were 22% lighter than WT controls”

IDOL-KO mice were also leaner when fed a high-fat diet that contained comparatively little cholesterol.

“however, the IDOL-KO mice were also leaner when fed a high-fat diet (HFD) that contained comparatively little cholesterol”

Two key orexigenic genes, Agrp and Npy, were downregulated in the AGRP neurons of IDOL-KO mice.

“two key orexigenic genes expressed were downregulated in the AGRP neurons of IDOL-KO mice: the genes encoding agouti-related peptide and neuropeptide Y”

Loss of VLDLR but not LDLR expression on an IDOL-KO background abolished the protective effects of IDOL deficiency on the development of obesity.

“Loss of VLDLR but not LDLR expression on an IDOL-KO background abolished the protective effects of IDOL deficiency on the development of obesity.”

IDOL KO and IDOL-LDLR DKO groups were indistinguishable with respect to body mass and adiposity on HFHC diet.

“Throughout the study, the IDOL KO and IDOL-LDLR DKO groups were indistinguishable with respect to body mass and adiposity (Fig. 3A, 3E).”

Intestine-specific IDOL knockout did not affect mass gain or adiposity.

“loss of IDOL activity in the intestine did not affect mass gain or adiposity (Fig. 2D, 2I)”

VLDLR single knockout mice and IDOL-VLDLR DKO mice showed comparable protection against adipose expansion upon high-fat diet feeding.

“The VLDLR single knockout mice and IDOL-VLDLR DKO showed comparable protection against adipose expansion upon high-fat diet feeding”

40 μg given by intracerebroventricular injection was the minimum dose required for maximal suppression of Idol expression in whole brain homogenates collected two weeks after injection.

“Dose-response studies determined that 40 μg given by intracerebroventricular injection was the minimum dose required for maximal suppression of Idol expression in whole brain homogenates collected two weeks after the injection”

Mice treated with the IDOL ASO weighed less than their control counterparts after six weeks on diet.

“The mice treated with the IDOL ASO weighed less than their control counterparts after six weeks on diet”

ASO-treated mice show reduced lipid accumulation in the liver by hematoxylin and eosin staining.

“Reduced lipid accumulation in the livers of ASO treated mice evident with hematoxylin and eosin staining of 5μm sections of liver (10x objective).”

Deletion of IDOL from neurons in the arcuate nucleus had no effect on body mass or food intake in mice fed a western diet for 12 weeks.

“Deletion of IDOL from neurons in the ARC had no effect on body mass or food intake for mice fed a western diet for 12 weeks”

• AssumptionRests on an assumption: Infection of neurons with AAV-hSyn-GFP-Cre in the arcuate nucleus or paraventricular nucleus of the hypothalamus successfully deletes IDOL in those neurons.

Long-term singly housed analysis revealed reduced food intake in the genetic absence of IDOL.

“analysis of mice housed singly over the course of weeks (WT, n=14; IDOL KO, n=12) revealed reduced food intake in the genetic absence of IDOL”

Neuron-specific virogenetic deletion of IDOL from individual hypothalamic nuclei is insufficient to protect against diet-induced obesity.

“Neuron-specific virogenetic deletion of IDOL from individual hypothalamic nuclei is insufficient to protect against diet-induced obesity.”

• AssumptionRests on an assumption: Infection of neurons with AAV-hSyn-GFP-Cre in the arcuate nucleus or paraventricular nucleus of the hypothalamus successfully deletes IDOL in those neurons.

Single cell RNA-seq demonstrated that deletion of IDOL altered the transcriptional landscape in several populations of neurons with well-established roles in the regulation of energy balance.

“Furthermore, our single cell RNA-seq study demonstrated that deletion of IDOL altered the transcriptional landscape in several populations of neurons with well-established roles in the regulation of energy balance.”

Idol knockdown in the CNS was associated with increased VLDLR protein in the hypothalamus.

“As expected, Idol knockdown in the CNS was associated with increased VLDLR protein in the hypothalamus”

Hepatic deletion of IDOL had no effect on obesity of mice challenged with the obesogenic HFHC diet.

“Hepatic deletion of IDOL had no effect on the obesity of mice challenged with the obesogenic HFHC diet (Fig. 2A, 2F)”

CreSynI Idolf/f mice had reduced mass and adiposity when challenged with the western diet.

“Similar to the global-KO mice, the CreSynIIdolf/f mice had reduced mass and adiposity when challenged with the western diet (Fig. 6A, 6B; n=18).”

Loss of liver IDOL did not confer protection against diet-induced metabolic dysfunction.

“We tested the role of IDOL in the liver directly with hepatocyte-specific conditional IDOL-KO mice (Albumin-Cre; Fig. 2) and found that loss of liver IDOL did not confer protection against diet-induced metabolic dysfunction.”

Western blot analysis of subcutaneous white adipose tissue showed enhanced phosphorylation of HSL in CreSynI Idolf/f mice.

“Western blot analysis of subcutaneous white adipose tissue showed enhanced phosphorylation of HSL in CreSynIIdolf/f mice (Fig. 6D).”

ASO-treated mice exhibited increased energy expenditure.

“The ASO-treated mice exhibited increased energy expenditure (Fig. 4F)”

The lean phenotype of CreR26/IDOL(AZ) mice was exaggerated when challenged with a high-fat high-cholesterol diet.

“The phenotype was exaggerated when the mice were challenged with a high-fat high-cholesterol diet (HFHC; Extended Data Fig. 1E).”

ASO treatment increased phosphorylation of hormone sensitive lipase in the subcutaneous white adipose depot.

“ASO treatment increased phosphorylation of hormone sensitive lipase in the subcutaneous white adipose depot (Fig. 4I)”

Vldlr gene expression had two clusters with significant numbers of cells with high Vldlr expression: oligodendrocytes and neurons.

“We analyzed the dataset for Vldlr gene expression and found two clusters with significant numbers of cells with high Vldlr expression: oligodendrocytes and neurons”

The consequence of IDOL deficiency is increased, rather than decreased, VLDLR protein levels.

“It is important to point out, however, that the consequence of IDOL deficiency is increased, rather than decreased, VLDLR protein levels.”

Adipose-specific deletion of IDOL in white and brown fat had no effect on mass or adiposity after 15 weeks of western-diet feeding.

“We challenged the mice with 15 weeks of western-diet feeding but saw no effect on mass or adiposity (Fig. 2B, 2G)”

At the end of the seven-week western diet study, Idol expression was suppressed by 65% in the hypothalamus of ASO-injected mice relative to vehicle-treated control mice.

“At the end of the seven-week western diet study, Idol expression was suppressed by 65% in the hypothalamus of ASO-injected mice relative to vehicle-treated control mice”

CreSynI Idolf/f mice consumed less food per week than their Idolf/f littermates.

“As shown in Fig. 6C, the CreSynIIdolf/f mice consumed less food per week than their Idolf/f littermates.”

No changes to food intake were observed in IDOL ASO-treated mice.

“Although IDOL ASO-treated mice phenocopied the whole-body IDOL KO mice, we did not observe changes to food intake.”

More modest differences were observed between genotypes in POMC and histaminergic neurons.

“More modest differences were observed between genotypes in POMC and histaminergic neurons”

Livers of the IDOL ASO-treated mice had less lipid deposition.

“Livers of the IDOL ASO-treated mice had less lipid deposition, similar to the global IDOL KO mice”

Differentially expressed genes identified in AGRP neurons showed enrichment of genes annotated in GWAS, OMIM or PubMed as associated with energy homeostasis.

“The differentially expressed genes identified in AGRP neurons showed an enrichment of these genes (Fig. 5D).”

Drop-seq identified twenty-six populations of cells in the hypothalamus, including eleven non-neuronal populations and fifteen distinct populations of neurons.

“Clustering algorithms successfully identified twenty-six populations of cells in the hypothalamus, including eleven non-neuronal populations and fifteen distinct populations of neurons”

18-month-old IDOL knockout mice are protected against age-induced adiposity.

“18-month-old IDOL KO mice are protected against age-induced adiposity.”

Deletion of IDOL leads to an over-abundance of VLDLR protein.

“deletion of IDOL, which leads to an over-abundance of VLDLR protein (Extended Data Fig. 4A, 4B)”

ASO treatment increased abundance of tyrosine hydroxylase in the BAT.

“and we noted increased abundance of tyrosine hydroxylase in the BAT (Fig. 4J), consistent with increased catecholamine production by sympathetic nerves.”

Deletion of IDOL from neurons in the paraventricular nucleus of the hypothalamus had no effect on body mass or food intake in mice fed a western diet for 12 weeks.

“Deletion of IDOL from neurons in the PVH had no effect on body mass or food intake for mice fed a western diet for 12 weeks”

• AssumptionRests on an assumption: Infection of neurons with AAV-hSyn-GFP-Cre in the arcuate nucleus or paraventricular nucleus of the hypothalamus successfully deletes IDOL in those neurons.

The treatment effect on energy expenditure was significant (p<0.05 by ANCOVA) when either overall mean total body mass or mean lean body mass was used as the covariate.

“The treatment effect was significant (p<0.05 by ANCOVA) when either the overall mean total body mass or the mean lean body mass of each treatment group was used as the covariate.”

Endothelial-specific IDOL knockout had no effect on the initiation or progression of obesity after WD for 15 weeks.

“Loss of IDOL activity in the endothelium had no effect on the initiation or progression of obesity after challenge with WD for 15 weeks (Fig. 2C, 2H).”

aP2-IDOL transgenic mice showed nearly complete ablation of VLDLR protein levels in both white and brown adipose depots.

“This line showed nearly complete ablation of VLDLR protein levels in both white and brown adipose depots, confirming the activation of the IDOL pathway”

There are no statistically significant differences in body composition at the onset of the CLAMS experiment between ASO-treated and control mice.

“No statistically significant differences in body composition at the onset of CLAMS experiment.”

Our data do not support a causal role for hepatic IDOL in the phenotype.

“By contrast, our data do not support a causal role for hepatic IDOL in the phenotype.”

IDOL affects energy balance not through its actions in peripheral metabolic tissues but by controlling lipoprotein receptor abundance in neurons.

“Unexpectedly, analysis of tissue-specific knockout mice revealed that IDOL affects energy balance, not through its actions in peripheral metabolic tissues (liver, adipose, endothelium, intestine, skeletal muscle), but by controlling lipoprotein receptor abundance in neurons.”

Deletion of IDOL in the CNS altered the transcriptional regulation of several key neural circuits known to regulate energy balance.

“Collectively, these data reveal that deletion of IDOL in the CNS altered the transcriptional regulation of several key neural circuits known to regulate energy balance.”

IDOL-mediated regulation of neuronal VLDL receptor is a previously unrecognized modulator of whole-body energy homeostasis.

“They further identify IDOL-mediated regulation of neuronal VLDL receptor as a previously unrecognized modulator of whole-body energy homeostasis.”

The relative importance of altered food intake to the phenotype was confirmed by thermoneutrality studies showing that body weight differences persisted when the role of thermogenesis was minimized.

“The relative importance of altered food intake to the phenotype was confirmed by thermoneutrality studies showing that body weight differences persisted when the role of thermogenesis was minimized.”

The changes in food intake in IDOL-deficient mice are the result of primary IDOL effects in neurons.

“This finding shows that the changes in food intake in IDOL-deficient mice are the result of primary IDOL effects in neurons.”

The observed changes in abundance of the histaminergic neuron population are likely an artifact of it being a relatively under-represented cluster even in wild-type mice.

“It is likely that the observed changes in cell abundance are an artifact of it being a relatively under-represented cluster even in the wild-type mice.”

If changes in whole-body energy expenditure were present in CreSynI Idolf/f mice, they were too subtle for the calorimeter to detect.

“however if changes in whole-body energy expenditure were present they were too subtle for the calorimeter to detect.”

The neuronal IDOL-VLDLR pathway has a role in metabolic homeostasis and diet-induced obesity.

“These studies identify a role for the neuronal IDOL-VLDLR pathway in metabolic homeostasis and diet-induced obesity.”

Two independent lines of global IDOL-KO mice exhibited a highly reproducible phenotype of resistance to diet-induced obesity.

“Two independent lines of global IDOL-KO mice (one derived at UCLA and one at AstraZeneca) exhibited a highly reproducible phenotype of resistance to diet-induced obesity.”

The appropriate balance of VLDLR protein levels in the CNS is important for the maintenance of whole-body energy homeostasis.

“Coupled with prior work, our results suggest that the appropriate balance of VLDLR protein levels in the CNS is important for the maintenance of whole-body energy homeostasis.”

Regulation of VLDLR protein levels is important for the maintenance of metabolic homeostasis.

“Collectively, these data provide strong evidence for the hypothesis that regulation of VLDLR protein levels is important for the maintenance of metabolic homeostasis.”

The liver is not the primary driver of the global IDOL-KO phenotype.

“LDLR is the only IDOL target expressed in the liver, further supporting the conclusion that the liver is not the primary driver of the global IDOL-KO phenotype.”

• AssumptionRests on an assumption: LDLR is the only IDOL target expressed in the liver.

Adipose-intrinsic actions of IDOL cannot explain the phenotype of global IDOL-knockout mice.

“Collectively the data collected from both gain- and loss-of-function mice lead us to conclude that adipose-intrinsic actions of IDOL cannot explain the phenotype of global IDOL-knockout mice.”

The protection against diet-induced obesity and metabolic dysfunction in IDOL-deficient mice is mediated by altered food intake and thermogenesis.

“Here we show that loss of IDOL in mice protects against the development of diet-induced obesity and metabolic dysfunction by altering food intake and thermogenesis.”

Activation of HSL indicates that deletion of IDOL from neurons affected peripheral energy homeostasis.

“The activation of HSL clearly indicates that deletion of IDOL from neurons affected peripheral energy homeostasis”

Altered abundance of the VLDLR receptor and not the LDLR is an important contributor to systemic energy balance.

“These data strongly suggest that altered abundance of the VLDLR receptor and not the LDLR is an important contributor to systemic energy balance.”

Changes in food intake were sufficient to affect body weight in the absence of energy expenditure differences.

“suggesting that changes in food intake were sufficient to affect body weight in the absence of energy expenditure differences”

VLDLR rather than LDLR is the primary mediator of IDOL effects on energy balance.

“Finally, we identify VLDLR rather than LDLR as the primary mediator of IDOL effects on energy balance.”

Acute knockdown of Idol in the central nervous system is linked to systemic changes in energy expenditure.

“These observations linked acute knockdown of Idol in the central nervous system to systemic changes in energy expenditure”

Tissue-specific studies pointed to the CNS as the primary site of IDOL action in the regulation of energy balance.

“Despite the abundant expression of IDOL and its targets in adipose tissue, tissue-specific studies pointed to the CNS as the primary site of IDOL action in the regulation of energy balance.”

VLDLR expression is required for the effects of IDOL on whole body metabolism.

“our finding that VLDLR expression is required for the effects of IDOL on whole body metabolism is consistent with prior work demonstrating that VLDLR is important to metabolic homeostasis.”

IDOL regulates systemic energy balance through the VLDL receptor.

“IDOL regulates systemic energy balance through the VLDL receptor.”

Complete loss of IDOL from neurons provided evidence that IDOL regulates food intake.

“The complete loss of IDOL from neurons provided evidence that IDOL regulates food intake, consistent with the reduced expression of Agrp and Npy seen in our single cell RNA-sequencing data of whole-body IDOL knockout mice.”

The IDOL-VLDLR pathway is a previously unrecognized mode of regulating whole-body energy homeostasis.

“Collectively, our studies identify the IDOL-VLDLR pathway as a previously unrecognized mode of regulating whole-body energy homeostasis.”

The marker panel used was sufficient to define all major cell types as well as neuronal subpopulations in the hypothalamus.

“These markers were sufficient to define all major cell types as well as neuronal subpopulations.”