ANGPTL8 Blockade With a Monoclonal Antibody Promotes Triglyceride Clearance, Energy Expenditure, and Weight Loss in Mice

Gusarova, Viktoria; Banfi, Serena; Alexa-Braun, Corey A.; Shihanian, Lisa M.; Mintah, Ivory J.; Lee, Joseph S.; Xin, Yurong; Su, Qi; Kamat, Vishal; Cohen, Jonathan C.; Hobbs, Helen H.; Zambrowicz, Brian; Yancopouloš, George D.; Murphy, Andrew; Gromada, Jesper

doi:10.1210/en.2016-1894

Cited by 59 publications

(62 citation statements)

References 17 publications

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“…In HFD-fed mice, there were subtle but matched decreases in both energy expenditure and food intake. These results contrast with a recent report that a monoclonal anti-ANGPTL8 antibody increased energy expenditure and weight loss [48], a difference which may be due to the different treatment modalities. The effects of Angptl8 ASO on body composition are intriguing.…”

Section: Discussioncontrasting

confidence: 99%

Angptl8 antisense oligonucleotide improves adipose lipid metabolism and prevents diet-induced NAFLD and hepatic insulin resistance in rodents

et al. 2018

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Aims/hypothesis Targeting regulators of adipose tissue lipoprotein lipase could enhance adipose lipid clearance, prevent ectopic lipid accumulation and consequently ameliorate insulin resistance and type 2 diabetes. Angiopoietin-like 8 (ANGPTL8) is an insulin-regulated lipoprotein lipase inhibitor strongly expressed in murine adipose tissue. However, Angptl8 knockout mice do not have improved insulin resistance. We hypothesised that pharmacological inhibition, using a second-generation antisense oligonucleotide (ASO) against Angptl8 in adult high-fat-fed rodents, would prevent ectopic lipid accumulation and insulin resistance by promoting adipose lipid uptake. Methods ANGPTL8 expression was assessed by quantitative PCR in omental adipose tissue of bariatric surgery patients. High-fatfed Sprague Dawley rats and C57BL/6 mice were treated with ASO against Angptl8 and insulin sensitivity was assessed by hyperinsulinaemic-euglycaemic clamps in rats and glucose tolerance tests in mice. Factors mediating lipid-induced hepatic insulin resistance were assessed, including lipid content, protein kinase Cε (PKCε) activation and insulin-stimulated Akt phosphorylation. Rat adipose lipid uptake was assessed by mixed meal tolerance tests. Murine energy balance was assessed by indirect calorimetry. Results Omental fat ANGPTL8 mRNA expression is higher in obese individuals with fatty liver and insulin resistance compared with BMI-matched insulin-sensitive individuals. Angptl8 ASO prevented hepatic steatosis, PKCε activation and hepatic insulin resistance in high-fat-fed rats. Postprandial triacylglycerol uptake in white adipose tissue was increased in Angptl8 ASO-treated rats. Angptl8 ASO protected high-fat-fed mice from glucose intolerance. Although there was no change in net energy balance, Angptl8 ASO increased fat mass in high-fat-fed mice. Conclusions/interpretation Disinhibition of adipose tissue lipoprotein lipase is a novel therapeutic modality to enhance adipose lipid uptake and treat non-alcoholic fatty liver disease and insulin resistance. In line with this, adipose ANGPTL8 is a candidate therapeutic target for these conditions.

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Section: Discussioncontrasting

confidence: 99%

Angptl8 antisense oligonucleotide improves adipose lipid metabolism and prevents diet-induced NAFLD and hepatic insulin resistance in rodents

et al. 2018

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“…Previous studies proposed that ANGPTL3 has weak effects on LPL on its own and that only the complex of ANGPTL3 with ANGPTL8 acts as a regulator of LPL activity (15,17,18). Our present results, together with our previous observations, demonstrate that the N-terminal ccd of ANGPTL3 is capable of inactivating LPL, even at substoichiometric concentrations, by catalyzing the unfolding of large parts of the catalytic domain (10,33).…”

Section: Discussionsupporting

confidence: 80%

“…In molar terms, ANGPTL3 is a relatively weak regulator of LPL in comparison to ANGPTL4 (10,15,16). Recent studies have shown, however, that the effect of ANGPTL3 on LPL is greatly enhanced by ANGPTL8 (15,17,18). ANGPTL8 is mostly produced in the liver and WAT and consists of a ccd, which is similar to those of ANGPTL3 and ANGPTL4, but ANGPTL8 is lacking a C-terminal, fibrinogen-like domain (6,7).…”

mentioning

confidence: 99%

On the mechanism of angiopoietin-like protein 8 for control of lipoprotein lipase activity

Kovrov

Kristensen

Larsson

et al. 2019

Journal of Lipid Research

148

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ANGPTL3, ANGPTL4, and ANGPTL8, are known to function as negative regulators of LPL activity in white adipose tissue (WAT), brown adipose tissue, and oxidative tissues (1-7). ANGPTL4, the most-studied family member, is expressed at various sites in the body (8). ANGPTL4 consists of an N-terminal coiled-coil domain (ccd) and a C-terminal, fibrinogen-like domain. The N-terminal ccd of ANGPTL4 inactivates LPL by promoting dissociation of the active LPL dimer into inactive monomers (9, 10). In this way, ANGPTL4 acts as a potent energy homeostasis switch causing reduced uptake of FAs from TG-rich lipoproteins in WAT during fasting (11,12). During physical activity or exercise, ANGPTL4 is upregulated in resting muscles, where it lowers LPL activity and thereby helps to direct FAs toward the contracting muscle tissue for energy production (13). In contrast to ANGPTL4, ANGPTL3 is mainly produced in the liver. It was previously demonstrated that the N-terminal ccd of ANGPTL3 reduces the activity of LPL in oxidative tissues in the fed state, thus directing the flow of lipoprotein-derived FAs to WAT for storage (14). In molar terms, ANGPTL3 is a relatively weak regulator of LPL in comparison to ANGPTL4 (10,15,16). Recent studies have shown, however, that the effect of ANGPTL3 on LPL is greatly enhanced by ANGPTL8 (15,17,18). ANGPTL8 is mostly produced in the liver and WAT and consists of a ccd, which is similar to those of ANGPTL3 and ANGPTL4, but ANGPTL8 is lacking a C-terminal, fibrinogen-like domain (6, 7). By itself, ANGPTL8 has no detectable effect on the activity of LPL. Reduction of LPL activity by ANGPTL8 occurs only in the presence of ANGPTL3 (15,18). It was recently demonstrated that ANGPTL8 needs to be coexpressed with ANGPTL3, by the same host cell, in order to have an effect on LPL activity (18).In this report, we show that recombinant ANGPTL8 produced in Escherichia coli has to be refolded together with Abstract Angiopoietin-like (ANGPTL) 8 is a secreted inhibitor of LPL, a key enzyme in plasma triglyceride metabolism. It was previously reported that ANGPTL8 requires another member of the ANGPTL family, ANGPTL3, to act on LPL. ANGPTL3, much like ANGPTL4, is a physiologically relevant regulator of LPL activity, which causes irreversible inactivation of the enzyme. Here, we show that ANGPTL8 can form complexes with either ANGPTL3 or ANGPTL4 when the proteins are refolded together from their denatured states. In contrast to the augmented inhibitory effect of the ANGPTL3/ ANGPTL8 complex on LPL activity, the ANGPTL4/ANGPTL8 complex is less active compared with ANGPTL4 alone. In our experiments, all three members of the ANGPTL family use the same mechanism to inactivate LPL, which involves dissociation of active dimeric LPL to monomers. This inactivation can be counteracted by the presence of glycosylphosphatidylinositol-anchored HDL binding protein 1, the endothelial LPL transport protein previously known to protect LPL from spontaneous and ANGPTL4-catalyzed inactivation. Our data demonstrate that ANGPTL8 may funct...

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“…Additionally, it is possible that increased energy expenditure, which we did not measure in the present study, promotes weight loss in some strains of mice lacking ANGPTL8. In support of this hypothesis, ANGPTL8 blockade with a monoclonal antibody increased energy expenditure and reduced weight gain in mice fed a high-fat high-cholesterol diet (19). Despite these differences, further study is required in animal models and humans to definitively determine the impact of ANGPTL8 ablation on both bodyweight and glucose metabolism.…”

Section: Discussionmentioning

confidence: 99%

The Metabolic Effects of Angiopoietin-like protein 8 (ANGPLT8) are Differentially Regulated by Insulin and Glucose in Adipose Tissue and Liver and are Controlled by AMPK Signaling

Zhang

Shannon

Bakewell

et al. 2019

Preprint

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Objective:The angiopoietin-like protein (ANGPTL) family represents a promising therapeutic target for dyslipidemia, which is a feature of obesity and type 2 diabetes (T2DM). The aim of the present study was to determine the metabolic role of ANGPTL8 and to investigate its nutritional, hormonal and molecular regulation in key metabolic tissues. Methods:The metabolism of ANGPTL8 knockout mice (ANGPTL8 -/-) was examined in mice following chow and high-fat diets (HFD). The regulation of ANGPTL8 expression by insulin and glucose was quantified using a combination of in vivo insulin clamp experiments in mice and in vitro experiments in hepatocytes and adipocytes. The role of AMPK signaling was examined, and the transcriptional control of ANGPTL8 was determined using bioinformatic and luciferase reporter approaches. Results:The ANGPTL8 -/mice had improved glucose tolerance and displayed reduced fed and fasted plasma triglycerides. However, there was no reduction in steatosis in ANGPTL8 -/mice after the HFD.Insulin acutely activated ANGPTL8 expression in liver and adipose tissue, which was mediated by C/EBPβ. Using insulin clamp experiments we observed that glucose further enhanced ANGPTL8 expression in the presence of insulin in adipocytes only. The activation of AMPK signaling potently suppressed the effect of insulin on ANGPTL8 expression in hepatocytes. Conclusion:These data show that ANGPTL8 plays an important metabolic role in mice that may extend beyond triglyceride metabolism. The finding that insulin and glucose have distinct roles in regulating ANGPTL8 expression in liver and adipose tissue may provide important clues about the function of ANGPTL8 in these tissues.

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ANGPTL8 Blockade With a Monoclonal Antibody Promotes Triglyceride Clearance, Energy Expenditure, and Weight Loss in Mice

Cited by 59 publications

References 17 publications

Angptl8 antisense oligonucleotide improves adipose lipid metabolism and prevents diet-induced NAFLD and hepatic insulin resistance in rodents

Angptl8 antisense oligonucleotide improves adipose lipid metabolism and prevents diet-induced NAFLD and hepatic insulin resistance in rodents

On the mechanism of angiopoietin-like protein 8 for control of lipoprotein lipase activity

The Metabolic Effects of Angiopoietin-like protein 8 (ANGPLT8) are Differentially Regulated by Insulin and Glucose in Adipose Tissue and Liver and are Controlled by AMPK Signaling

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