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Regulation of plasma triglyceride partitioning by adipose-derived ANGPTL4 in mice

Spitler, Kathryn M., Shetty, Shwetha K., Cushing, Emily M., Sylvers-Davie, Kelli L., Davies, Brandon S. J.·2021·Scientific Reports
DOI 10.1038/s41598-021-87020-5PMC PMC8041937
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Abstract

Elevated plasma triglyceride levels are associated with metabolic disease. Angiopoietin-like protein 4 (ANGPTL4) regulates plasma triglyceride levels by inhibiting lipoprotein lipase (LPL). Our aim was to investigate the role of adipocyte-specific deficiency of ANGPTL4 in mice during high fat diet feeding. Adipocyte-specific ANGPTL4 deficient mice were fed a high fat diet (60% kCal from fat) for either 12 weeks or 6 months. We performed plasma metabolic measurements, triglyceride clearance and uptake assays, LPL activity assays, and assessed glucose homeostasis. Mice lacking adipocyte ANGPTL4 recapitulated the triglyceride phenotypes of whole-body ANGPTL4 deficiency, including increased adipose LPL activity, lower plasma triglyceride levels, and increased uptake of triglycerides into adipose tissue. When fed a high fat diet (HFD), these mice continued to display enhanced adipose LPL activity and initially had improved glucose and insulin sensitivity. However, after 6 months on HFD, the improvements in glucose homeostasis were largely lost. Moreover, despite higher adipose LPL activity levels, mice lacking adipocyte ANGPTL4 no longer had increased triglyceride uptake into adipose compared to littermate controls after chronic high-fat feeding. These observations suggest that after chronic high-fat feeding LPL is no longer rate-limiting for triglyceride delivery to adipocytes. We conclude that while adipocyte-derived ANGPTL4 is an important regulator of plasma triglyceride levels and triglyceride partitioning under normal diet conditions, its role is diminished after chronic high-fat feeding.

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Figures

Figure 1 Characterization of mice with adipocyte-specific deletion of Angptl4. (a) mRNA expression of Angptl4 in liver, heart, quadriceps muscle (quad), gonadal white adipose tissue (gWAT), subcutaneous white adipose tissue (sWAT), and brown adipose tissues (BAT) from 8–12 week old female Angptl4fl/fl (n = 8) and Angptl4AdipoKO (n = 8) mice following a 6 h fast (mean ± SEM). (b–d) Fasting plasma triglyceride (b), non-esterified fatty acid (c), and blood glucose (d) levels in 8–12 week male and female Angptl4fl/fl and Angptl4AdipoKO mice following a 6 h fast (mean ± SEM; n = 7–11). (e, f) Fasted (6 h) female Angptl4fl/fl (n = 8) and Angptl4AdipoKO (n = 7) mice were injected intravenously with 3H-triglyceride–containing chylomicrons. (e) Clearance of radiolabel from the plasma 1, 5, 10, and 15 min after injection. Points represent percentage of radiolabel remaining in the plasma at the indicated time points compared to the 1 min time point (mean ± SEM). (f) Uptake of radiolabel after 15 min (% injected dose/g tissue) into the indicated tissues (mean ± SEM). (g) Heart, quadricep muscle (quad), gonadal white adipose tissue (gWAT), subcutaneous adipose tissue (sWAT), and brown adipose (BAT) tissue from fasted (6 h) female Angptl4fl/fl and Angptl4AdipoKO mice were harvested and lipase activity was measured (n = 6–9/group). (h) Liver was harvested from fasted (6 h) female Angptl4fl/fl and Angptl4AdipoKO mice (n = 8/group). Lipase activity was measured in the presence or absence of 1 M-NaCl to distinguish between hepatic and lipoprotein lipase. Bars show relative lipase activity in each tissue normalized to Angptl4fl/fl (mean ± SEM). *p < 0.05, **p < 0.01, ***p < 0.001 by t-test analysis (panels a–c, f, g) or repeated measures ANOVA (panel e).
Figure 1 Characterization of mice with adipocyte-specific deletion of Angptl4. (a) mRNA expression of Angptl4 in liver, heart, quadriceps muscle (quad), gonadal white adipose tissue (gWAT), subcutaneous white adipose tissue (sWAT), and brown adipose tissues (BAT) from 8–12 week old female Angptl4fl/fl (n = 8) and Angptl4AdipoKO (n = 8) mice following a 6 h fast (mean ± SEM). (b–d) Fasting plasma triglyceride (b), non-esterified fatty acid (c), and blood glucose (d) levels in 8–12 week male and female Angptl4fl/fl and Angptl4AdipoKO mice following a 6 h fast (mean ± SEM; n = 7–11). (e, f) Fasted (6 h) female Angptl4fl/fl (n = 8) and Angptl4AdipoKO (n = 7) mice were injected intravenously with 3H-triglyceride–containing chylomicrons. (e) Clearance of radiolabel from the plasma 1, 5, 10, and 15 min after injection. Points represent percentage of radiolabel remaining in the plasma at the indicated time points compared to the 1 min time point (mean ± SEM). (f) Uptake of radiolabel after 15 min (% injected dose/g tissue) into the indicated tissues (mean ± SEM). (g) Heart, quadricep muscle (quad), gonadal white adipose tissue (gWAT), subcutaneous adipose tissue (sWAT), and brown adipose (BAT) tissue from fasted (6 h) female Angptl4fl/fl and Angptl4AdipoKO mice were harvested and lipase activity was measured (n = 6–9/group). (h) Liver was harvested from fasted (6 h) female Angptl4fl/fl and Angptl4AdipoKO mice (n = 8/group). Lipase activity was measured in the presence or absence of 1 M-NaCl to distinguish between hepatic and lipoprotein lipase. Bars show relative lipase activity in each tissue normalized to Angptl4fl/fl (mean ± SEM). *p < 0.05, **p < 0.01, ***p < 0.001 by t-test analysis (panels a–c, f, g) or repeated measures ANOVA (panel e).CC BY · PubMed Central
Figure 2 Body weights, fat mass, and metabolic phenotypes of Angptl4fl/fl and Angptl4AdipoKO mice. (a) Weekly body weights of male Angptl4fl/fl and Angptl4AdipoKO mice fed either a normal chow diet (NCD) or a high fat diet (HFD; 60% by kCal) for 12 weeks starting at 8 weeks of age (mean ± SEM; n = 12–19/group). (b) Tissues weights of heart, liver, kidney, quadriceps muscle (quad), epididymal white adipose (eWAT), subcutaneous white adipose tissue (sWAT), and brown adipose tissue (BAT) in male Angptl4fl/fl and Angptl4AdipoKO mice after 12 weeks on diet (mean ± SEM; n = 7–11group). (c) Lean muscle and fat mass of male Angptl4fl/fl and Angptl4AdipoKO mice as measured by NMR after 12 weeks on diet (mean ± SEM; n = 6–9/group). Plasma triglycerides (d), plasma non-esterified fatty acids (e), blood glucose (f), and liver triglycerides (g) of fasted (6 h) male Angptl4fl/fl and Angptl4AdipoKO mice at the end of 12 weeks on diet (mean ± SEM; n = 5–8/group). ###p < 0.001 for dietary differences by two-way ANOVA. *p < 0.05, **p < 0.01 for individual genotype-specific differences by multiple comparison after two-way ANOVA (Tukey correction).
Figure 2 Body weights, fat mass, and metabolic phenotypes of Angptl4fl/fl and Angptl4AdipoKO mice. (a) Weekly body weights of male Angptl4fl/fl and Angptl4AdipoKO mice fed either a normal chow diet (NCD) or a high fat diet (HFD; 60% by kCal) for 12 weeks starting at 8 weeks of age (mean ± SEM; n = 12–19/group). (b) Tissues weights of heart, liver, kidney, quadriceps muscle (quad), epididymal white adipose (eWAT), subcutaneous white adipose tissue (sWAT), and brown adipose tissue (BAT) in male Angptl4fl/fl and Angptl4AdipoKO mice after 12 weeks on diet (mean ± SEM; n = 7–11group). (c) Lean muscle and fat mass of male Angptl4fl/fl and Angptl4AdipoKO mice as measured by NMR after 12 weeks on diet (mean ± SEM; n = 6–9/group). Plasma triglycerides (d), plasma non-esterified fatty acids (e), blood glucose (f), and liver triglycerides (g) of fasted (6 h) male Angptl4fl/fl and Angptl4AdipoKO mice at the end of 12 weeks on diet (mean ± SEM; n = 5–8/group). ###p < 0.001 for dietary differences by two-way ANOVA. *p < 0.05, **p < 0.01 for individual genotype-specific differences by multiple comparison after two-way ANOVA (Tukey correction).CC BY · PubMed Central
Figure 3 Chylomicron clearance and uptake and lipase activity in Angptl4AdipoKO mice. (a, b) At the conclusion of 12 weeks of either normal chow diet (NCD) or high fat diet (HFD) Angptl4fl/fl and Angptl4AdipoKO male mice (n = 7–10/group) were fasted (6 h) and injected intravenously with 3H-triglyceride–containing chylomicrons. (a) Clearance of radiolabel from the plasma 1, 5, 10, and 15 min after injection. Points represent percentage of radiolabel remaining in the plasma at the indicated time points compared to the 1-min time point (mean ± SEM). *p < 0.05 by repeated measures ANOVA. (b) Uptake of radiolabel (% injected dose/g tissue) into the indicated tissues after 15 min (mean ± SEM). ##p < 0.01 for dietary differences by two-way ANOVA. *p < 0.05, ***p < 0.001 for individual genotype-specific differences by multiple comparison after two-way ANOVA (Tukey correction). (c) Heart, quadricep muscle (quad), epididymal adipose tissue (eWAT), subcutaneous adipose tissue (sWAT), and brown adipose (BAT) tissue from fasted (6 h) male Angptl4fl/fl and Angptl4AdipoKO mice were harvested and lipase activity was measured (n = 6–8/group). (d, e) Liver was harvested from fasted (6 h) male Angptl4fl/fl and Angptl4AdipoKO mice (d, NCD groups and e, HFD groups) (n = 6/group). Lipase activity was measured in the presence or absence of 1 M NaCl to distinguish between hepatic and lipoprotein lipase. Bars show relative lipase activity in each tissue normalized to Angptl4fl/fl (mean ± SEM). #p < 0.05, ##p < 0.01, ###p < 0.001 for dietary differences by two-way ANOVA. ***p < 0.001 for individual genotype-specific differences by multiple comparison after two-way ANOVA (Tukey correction).
Figure 3 Chylomicron clearance and uptake and lipase activity in Angptl4AdipoKO mice. (a, b) At the conclusion of 12 weeks of either normal chow diet (NCD) or high fat diet (HFD) Angptl4fl/fl and Angptl4AdipoKO male mice (n = 7–10/group) were fasted (6 h) and injected intravenously with 3H-triglyceride–containing chylomicrons. (a) Clearance of radiolabel from the plasma 1, 5, 10, and 15 min after injection. Points represent percentage of radiolabel remaining in the plasma at the indicated time points compared to the 1-min time point (mean ± SEM). *p < 0.05 by repeated measures ANOVA. (b) Uptake of radiolabel (% injected dose/g tissue) into the indicated tissues after 15 min (mean ± SEM). ##p < 0.01 for dietary differences by two-way ANOVA. *p < 0.05, ***p < 0.001 for individual genotype-specific differences by multiple comparison after two-way ANOVA (Tukey correction). (c) Heart, quadricep muscle (quad), epididymal adipose tissue (eWAT), subcutaneous adipose tissue (sWAT), and brown adipose (BAT) tissue from fasted (6 h) male Angptl4fl/fl and Angptl4AdipoKO mice were harvested and lipase activity was measured (n = 6–8/group). (d, e) Liver was harvested from fasted (6 h) male Angptl4fl/fl and Angptl4AdipoKO mice (d, NCD groups and e, HFD groups) (n = 6/group). Lipase activity was measured in the presence or absence of 1 M NaCl to distinguish between hepatic and lipoprotein lipase. Bars show relative lipase activity in each tissue normalized to Angptl4fl/fl (mean ± SEM). #p < 0.05, ##p < 0.01, ###p < 0.001 for dietary differences by two-way ANOVA. ***p < 0.001 for individual genotype-specific differences by multiple comparison after two-way ANOVA (Tukey correction).CC BY · PubMed Central
Figure 4 Glucose tolerance and insulin sensitivity of Angptl4AdipoKO mice. (a) Glucose tolerance tests were performed on fasted (6 h) male Angptl4fl/fl and Angptl4AdipoKO mice after 11 weeks of either a normal chow diet (NCD) or high fat diet (HFD). Blood glucose concentrations were measured over 2 h after injection with glucose. Points represent glucose levels (mean ± SEM; n = 8–11) at each respective time point. *p < 0.05 by repeated measures ANOVA. Bar graphs represent area under the curve (mean ± SEM) for all time points. ###p < 0.001 for dietary differences by two-way ANOVA. (b) Insulin tolerance tests were performed on fasted (4 h) male Angptl4fl/fl and Angptl4AdipoKO mice after 12 weeks on diet. Blood glucose concentrations were measured over 90 min after injection with insulin. Points represent glucose levels (mean ± SEM; n = 9–10) at each respective time point. **p < 0.01 for individual genotype-specific differences by repeated measures ANOVA. Bar graphs represent area under the curve (mean ± SEM) for all time points. ###p < 0.001 for dietary differences by two-way ANOVA. **p < 0.01 for individual genotype-specific differences by multiple comparison after two-way ANOVA (Tukey correction).
Figure 4 Glucose tolerance and insulin sensitivity of Angptl4AdipoKO mice. (a) Glucose tolerance tests were performed on fasted (6 h) male Angptl4fl/fl and Angptl4AdipoKO mice after 11 weeks of either a normal chow diet (NCD) or high fat diet (HFD). Blood glucose concentrations were measured over 2 h after injection with glucose. Points represent glucose levels (mean ± SEM; n = 8–11) at each respective time point. *p < 0.05 by repeated measures ANOVA. Bar graphs represent area under the curve (mean ± SEM) for all time points. ###p < 0.001 for dietary differences by two-way ANOVA. (b) Insulin tolerance tests were performed on fasted (4 h) male Angptl4fl/fl and Angptl4AdipoKO mice after 12 weeks on diet. Blood glucose concentrations were measured over 90 min after injection with insulin. Points represent glucose levels (mean ± SEM; n = 9–10) at each respective time point. **p < 0.01 for individual genotype-specific differences by repeated measures ANOVA. Bar graphs represent area under the curve (mean ± SEM) for all time points. ###p < 0.001 for dietary differences by two-way ANOVA. **p < 0.01 for individual genotype-specific differences by multiple comparison after two-way ANOVA (Tukey correction).CC BY · PubMed Central
Figure 5 Body weights, fat mass, and metabolic phenotypes of Angptl4fl/fl and Angptl4AdipoKO mice after chronic high-fat feeding. (a) Weekly body weights of male Angptl4fl/fl and Angptl4AdipoKO mice fed either a normal chow diet (NCD) or high fat diet (HFD) for 6 months starting at 8 weeks of age (mean ± SEM; n = 10–17/group). *p < 0.05 by repeated measures ANOVA. (b) Tissues weights of heart, liver, kidney, quadriceps muscle (quad), epididymal white adipose (eWAT), subcutaneous white adipose tissue (sWAT), and brown adipose tissue (BAT) in male Angptl4fl/fl and Angptl4AdipoKO mice after 6 months on diet (mean ± SEM; n = 8–13/group). (c) Lean muscle mass and fat mass of male Angptl4fl/fl and Angptl4AdipoKO mice as measured by NMR after 24 weeks on diet. (mean ± SEM; n = 11–14/group). Plasma triglycerides (d), plasma non-esterified fatty acids (e), blood glucose (f), and liver triglycerides (g) of fasted (6 h) male Angptl4fl/fl and Angptl4AdipoKO mice after 6 months on diet (mean ± SEM; n = 8–9/group). ##p < 0.01, ###p < 0.001 for dietary differences by two-way ANOVA. *p < 0.05,***p < 0.001 for individual genotype-specific differences by multiple comparison after two-way ANOVA (Tukey correction).
Figure 5 Body weights, fat mass, and metabolic phenotypes of Angptl4fl/fl and Angptl4AdipoKO mice after chronic high-fat feeding. (a) Weekly body weights of male Angptl4fl/fl and Angptl4AdipoKO mice fed either a normal chow diet (NCD) or high fat diet (HFD) for 6 months starting at 8 weeks of age (mean ± SEM; n = 10–17/group). *p < 0.05 by repeated measures ANOVA. (b) Tissues weights of heart, liver, kidney, quadriceps muscle (quad), epididymal white adipose (eWAT), subcutaneous white adipose tissue (sWAT), and brown adipose tissue (BAT) in male Angptl4fl/fl and Angptl4AdipoKO mice after 6 months on diet (mean ± SEM; n = 8–13/group). (c) Lean muscle mass and fat mass of male Angptl4fl/fl and Angptl4AdipoKO mice as measured by NMR after 24 weeks on diet. (mean ± SEM; n = 11–14/group). Plasma triglycerides (d), plasma non-esterified fatty acids (e), blood glucose (f), and liver triglycerides (g) of fasted (6 h) male Angptl4fl/fl and Angptl4AdipoKO mice after 6 months on diet (mean ± SEM; n = 8–9/group). ##p < 0.01, ###p < 0.001 for dietary differences by two-way ANOVA. *p < 0.05,***p < 0.001 for individual genotype-specific differences by multiple comparison after two-way ANOVA (Tukey correction).CC BY · PubMed Central
Figure 6 Chylomicron clearance and uptake and lipase activity in Angptl4AdipoKO mice after chronic high-fat feeding. At the conclusion of 6 months of either normal chow diet (NCD) or high fat diet (HFD) Angptl4fl/fl and Angptl4AdipoKO male mice (n = 7–9/group) were fasted (6 h) and injected intravenously with 3H-triglyceride containing chylomicrons. (a) Clearance of radiolabel from the plasma 1, 5, 10, and 15 min after injection. Points represent percentage of radiolabel remaining in the plasma at the indicated time points compared to the 1-min time point (mean ± SEM). ***p < 0.001 by repeated measures ANOVA. (b) Uptake of radiolabel (% injected dose/g tissue) into the indicated tissues after 15 min (mean ± SEM). #p < 0.05, ##p < 0.01, ###p < 0.001 for dietary differences by two-way ANOVA. *p < 0.05, ***p < 0.001 for individual genotype-specific differences by multiple comparison after two-way ANOVA. (c) Heart, quadricep muscle (quad), epididymal adipose tissue (eWAT), subcutaneous adipose tissue (sWAT), and brown adipose (BAT) tissue from fasted (6 h) male Angptl4fl/fl and Angptl4AdipoKO mice were harvested and lipase activity was measured (n = 6–8/group). (d, e) Liver was harvested from fasted (6 h) male Angptl4fl/fl and Angptl4AdipoKO mice (d, NCD groups and e, HFD groups)(n = 6–9/group). Lipase activity was measured in the presence or absence of 1 M NaCl to distinguish between hepatic and lipoprotein lipase. Bars show relative lipase activity in each tissue normalized to Angptl4fl/fl (mean ± SEM). #p < 0.05, ##p < 0.01, ###p < 0.001 for dietary differences by two-way ANOVA. *p < 0.05, **p < 0.01 ***p < 0.001 for individual genotype-specific differences by multiple comparison after two-way ANOVA.
Figure 6 Chylomicron clearance and uptake and lipase activity in Angptl4AdipoKO mice after chronic high-fat feeding. At the conclusion of 6 months of either normal chow diet (NCD) or high fat diet (HFD) Angptl4fl/fl and Angptl4AdipoKO male mice (n = 7–9/group) were fasted (6 h) and injected intravenously with 3H-triglyceride containing chylomicrons. (a) Clearance of radiolabel from the plasma 1, 5, 10, and 15 min after injection. Points represent percentage of radiolabel remaining in the plasma at the indicated time points compared to the 1-min time point (mean ± SEM). ***p < 0.001 by repeated measures ANOVA. (b) Uptake of radiolabel (% injected dose/g tissue) into the indicated tissues after 15 min (mean ± SEM). #p < 0.05, ##p < 0.01, ###p < 0.001 for dietary differences by two-way ANOVA. *p < 0.05, ***p < 0.001 for individual genotype-specific differences by multiple comparison after two-way ANOVA. (c) Heart, quadricep muscle (quad), epididymal adipose tissue (eWAT), subcutaneous adipose tissue (sWAT), and brown adipose (BAT) tissue from fasted (6 h) male Angptl4fl/fl and Angptl4AdipoKO mice were harvested and lipase activity was measured (n = 6–8/group). (d, e) Liver was harvested from fasted (6 h) male Angptl4fl/fl and Angptl4AdipoKO mice (d, NCD groups and e, HFD groups)(n = 6–9/group). Lipase activity was measured in the presence or absence of 1 M NaCl to distinguish between hepatic and lipoprotein lipase. Bars show relative lipase activity in each tissue normalized to Angptl4fl/fl (mean ± SEM). #p < 0.05, ##p < 0.01, ###p < 0.001 for dietary differences by two-way ANOVA. *p < 0.05, **p < 0.01 ***p < 0.001 for individual genotype-specific differences by multiple comparison after two-way ANOVA.CC BY · PubMed Central
Figure 7 Glucose tolerance and insulin sensitivity of Angptl4AdipoKO mice after chronic high fat feeding. (a) Glucose tolerance tests were performed on fasted (6 h) male Angptl4fl/fl and Angptl4AdipoKO mice after 24 weeks of either a normal chow diet (NCD) or high fat diet (HFD). Blood glucose concentrations were measured over 2 h after injection with glucose. Points represent glucose levels (mean ± SEM; n = 9–10) at each respective time point. Bar graphs represent area under the curve (mean ± SEM) for all time points. (b) Insulin tolerance tests were performed on fasted (4 h) male Angptl4fl/fl and Angptl4AdipoKO mice after 25 weeks of either a normal chow diet (NCD) or high fat diet (HFD). Blood glucose concentrations were measured over 90 min after injection with insulin. Points represent glucose levels (mean ± SEM; n = 9–10) at each respective time point. *p < 0.05 by repeated measures ANOVA. Bar graphs represent area under the curve (mean ± SEM) for all time points. ###p < 0.001 for dietary differences by two-way ANOVA.
Figure 7 Glucose tolerance and insulin sensitivity of Angptl4AdipoKO mice after chronic high fat feeding. (a) Glucose tolerance tests were performed on fasted (6 h) male Angptl4fl/fl and Angptl4AdipoKO mice after 24 weeks of either a normal chow diet (NCD) or high fat diet (HFD). Blood glucose concentrations were measured over 2 h after injection with glucose. Points represent glucose levels (mean ± SEM; n = 9–10) at each respective time point. Bar graphs represent area under the curve (mean ± SEM) for all time points. (b) Insulin tolerance tests were performed on fasted (4 h) male Angptl4fl/fl and Angptl4AdipoKO mice after 25 weeks of either a normal chow diet (NCD) or high fat diet (HFD). Blood glucose concentrations were measured over 90 min after injection with insulin. Points represent glucose levels (mean ± SEM; n = 9–10) at each respective time point. *p < 0.05 by repeated measures ANOVA. Bar graphs represent area under the curve (mean ± SEM) for all time points. ###p < 0.001 for dietary differences by two-way ANOVA.CC BY · PubMed Central

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Citations

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Metadata

Authors
Spitler, K. M., Shetty, S. K., Cushing, E. M., Sylvers-Davie, K. L., & Davies, B. S. J.
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2021-04-12
Volume
11
Issue
1
ISSN
2045-2322
DOI
10.1038/s41598-021-87020-5
PMC
PMC8041937
Cited by
42
References
8
Language
en
Licence
Funders
NIH (R01HL130146)

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.

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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