Mice lacking ANGPTL8 (Betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis
01 Oct 2013-Proceedings of the National Academy of Sciences of the United States of America (National Academy of Sciences)-Vol. 110, Iss: 40, pp 16109-16114
TL;DR: The data indicate that ANGPTL8 plays a key role in the metabolic transition between fasting and refeeding; it is required to direct fatty acids to adipose tissue for storage in the fed state.
Abstract: Angiopoietin-like protein (ANGPTL)8 (alternatively called TD26, RIFL, Lipasin, and Betatrophin) is a newly recognized ANGPTL family member that has been implicated in both triglyceride (TG) and glucose metabolism. Hepatic overexpression of ANGPTL8 causes hypertriglyceridemia and increased insulin secretion. Here we examined the effects of inactivating Angptl8 on TG and glucose metabolism in mice. Angptl8 knockout (Angptl8−/−) mice gained weight more slowly than wild-type littermates due to a selective reduction in adipose tissue accretion. Plasma levels of TGs of the Angptl8−/− mice were similar to wild-type animals in the fasted state but paradoxically decreased after refeeding. The lower TG levels were associated with both a reduction in very low density lipoprotein secretion and an increase in lipoprotein lipase (LPL) activity. Despite the increase in LPL activity, the uptake of very low density lipoprotein-TG is markedly reduced in adipose tissue but preserved in hearts of fed Angptl8−/− mice. Taken together, these data indicate that ANGPTL8 plays a key role in the metabolic transition between fasting and refeeding; it is required to direct fatty acids to adipose tissue for storage in the fed state. Finally, glucose and insulin tolerance testing revealed no alterations in glucose homeostasis in mice fed either a chow or high fat diet. Thus, although absence of ANGPTL8 profoundly disrupts TG metabolism, we found no evidence that it is required for maintenance of glucose homeostasis.
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TL;DR: The interplay of the pancreas with various other organs and tissues that maintain glucose homeostasis is summarized and anti-diabetic drugs and their impact on signaling pathways underlying the network will be discussed.
Abstract: In order to ensure normal body function, the human body is dependent on a tight control of its blood glucose levels. This is accomplished by a highly sophisticated network of various hormones and neuropeptides released mainly from the brain, pancreas, liver, intestine as well as adipose and muscle tissue. Within this network, the pancreas represents a key player by secreting the blood sugar-lowering hormone insulin and its opponent glucagon. However, disturbances in the interplay of the hormones and peptides involved may lead to metabolic disorders such as type 2 diabetes mellitus (T2DM) whose prevalence, comorbidities and medical costs take on a dramatic scale. Therefore, it is of utmost importance to uncover and understand the mechanisms underlying the various interactions to improve existing anti-diabetic therapies and drugs on the one hand and to develop new therapeutic approaches on the other. This review summarizes the interplay of the pancreas with various other organs and tissues that maintain glucose homeostasis. Furthermore, anti-diabetic drugs and their impact on signaling pathways underlying the network will be discussed.
537 citations
TL;DR: It is now evident that most of the physiological variation in LPL activity, such as during fasting and exercise, appears to be driven via post-translational mechanisms by extracellular proteins.
400 citations
Cites background from "Mice lacking ANGPTL8 (Betatrophin) ..."
...of ANGPTL8 lowers plasma TG [85], whereas overexpression of...
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TL;DR: It is reported that Angptl8(?/?) mice undergo entirely normal beta cell expansion in response to insulin resistance resulting from either a high-fat diet or from the administration of the insulin receptor antagonist S961, which indicates that inhibition of ANGPTL8 represents a therapeutic strategy for hypertriglyceridemia.
204 citations
Cites background or methods or result from "Mice lacking ANGPTL8 (Betatrophin) ..."
...Angptl8 / mice (75% C57BL/6NTac and 25% 129/SvEvTac background) were generated by homologous recombination using Regeneron’s VelociGene technology as previously described (Wang et al., 2013)....
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...Animals Angptl8 / mice (75% C57BL/6NTac and 25% 129/SvEvTac background) were generated by homologous recombination using Regeneron’s VelociGene technology as previously described (Wang et al., 2013)....
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...It had previously been reported that wild-type and Angptl8 / mice show no difference in glucose homeostasis (Wang et al., 2013)....
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...It had previously been reported that wild-type and Angptl8 / mice show no difference in glucose homeostasis (Wang et al., 2013)....
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...ANGPTL8 Does Not Regulate Beta Cell Function or Growth in Response to High-Fat Diet-Induced Insulin Resistance Mice lacking ANGPTL8 had normal nonfasted plasma glucose and insulin levels, but only one-third of the circulating triglycerides of wild-type mice (Figures 1A–1C), as reported previously (Wang et al., 2013)....
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TL;DR: Serum lipasin/betatrophin is nutritionally-regulated hepatokine that is increased in human type 2 diabetes and obesity and showed a 35% increase 2 hours following a defined meal.
Abstract: Lipasin (also known as C19ORF80, RIFL, ANGPTL8 and betatrophin) is a newly discovered circulating factor that regulates lipid metabolism and promotes pancreatic β-cell proliferation. Whether circulating levels of lipasin in humans are altered in a) type 2 diabetes; b) obesity and c) the postprandial state, however, is unknown. The current study aimed to compare serum lipasin levels in those who were a) non-diabetic (N=15) or diabetic (BMI- and age-matched; N=14); b) lean or obese (N=53 totally) and c) fasting and 2 hours following a defined meal (N=12). Serum lipasin levels were determined by the enzyme-linked immunosorbent assay. Lipasin levels [mean±SEM] were increased by more than two fold (P<0.001) in the diabetic patients (5.56±0.73 ng/mL) as compared to the control subjects (2.19±0.24 ng/mL). Serum lipasin levels were positively correlated with BMI (rho=0.49, P<0.001), and showed a 35% increase 2 hours following a defined meal (P=0.009). Therefore, lipasin/betatrophin is nutritionally-regulated hepatokine that is increased in human type 2 diabetes and obesity.
203 citations
TL;DR: The diverse signaling mediators and mechanisms adipose tissue utilizes to relay information to other organs are reviewed and recently identified adipokines (proteins, lipids, and metabolites) are discussed and the contributions of noncoding RNAs and EVs to the ever-increasing complexities of adipose tissues inter-organ communication are outlined.
172 citations
References
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TL;DR: The complex, interdigitated roles of these three SREBPs have been dissected through the study of ten different lines of gene-manipulated mice and form the subject of this review.
Abstract: Lipid homeostasis in vertebrate cells is regulated by a family of membrane-bound transcription factors designated sterol regulatory element–binding proteins (SREBPs). SREBPs directly activate the expression of more than 30 genes dedicated to the synthesis and uptake of cholesterol, fatty acids, triglycerides, and phospholipids, as well as the NADPH cofactor required to synthesize these molecules (1–4). In the liver, three SREBPs regulate the production of lipids for export into the plasma as lipoproteins and into the bile as micelles. The complex, interdigitated roles of these three SREBPs have been dissected through the study of ten different lines of gene-manipulated mice. These studies form the subject of this review.
4,406 citations
"Mice lacking ANGPTL8 (Betatrophin) ..." refers background in this paper
...No changes were observed in the mRNAs encoding the transcription factors ChREBP and SREBP-1c, which coordinate the expression of genes required for fatty acid synthesis (20, 21), or in the expression of enzymes that catalyze the synthesis of fatty acids....
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...The conversion of carbohydrates to fatty acids is orchestrated by the transcription factors sterol regulatory element binding protein 1 (SREBP1c) and carbohydrate response element binding protein (ChREBP), which promote the transcription of enzymes required for de novo lipogenesis in response to insulin (21, 25)....
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TL;DR: Overall, LPL is a fascinating enzyme that contributes in a pronounced way to normal lipoprotein metabolism, tissue-specific substrate delivery and utilization, and the many aspects of obesity and other metabolic disorders that relate to energy balance, insulin action, and body weight regulation.
Abstract: Lipoprotein lipase (LPL) is a multifunctional enzyme produced by many tissues, including adipose tissue, cardiac and skeletal muscle, islets, and macrophages. LPL is the rate-limiting enzyme for the hydrolysis of the triglyceride (TG) core of circulating TG-rich lipoproteins, chylomicrons, and very low-density lipoproteins (VLDL). LPL-catalyzed reaction products, fatty acids, and monoacylglycerol are in part taken up by the tissues locally and processed differentially; e.g., they are stored as neutral lipids in adipose tissue, oxidized, or stored in skeletal and cardiac muscle or as cholesteryl ester and TG in macrophages. LPL is regulated at transcriptional, posttranscriptional, and posttranslational levels in a tissue-specific manner. Nutrient states and hormonal levels all have divergent effects on the regulation of LPL, and a variety of proteins that interact with LPL to regulate its tissue-specific activity have also been identified. To examine this divergent regulation further, transgenic and knockout murine models of tissue-specific LPL expression have been developed. Mice with overexpression of LPL in skeletal muscle accumulate TG in muscle, develop insulin resistance, are protected from excessive weight gain, and increase their metabolic rate in the cold. Mice with LPL deletion in skeletal muscle have reduced TG accumulation and increased insulin action on glucose transport in muscle. Ultimately, this leads to increased lipid partitioning to other tissues, insulin resistance, and obesity. Mice with LPL deletion in the heart develop hypertriglyceridemia and cardiac dysfunction. The fact that the heart depends increasingly on glucose implies that free fatty acids are not a sufficient fuel for optimal cardiac function. Overall, LPL is a fascinating enzyme that contributes in a pronounced way to normal lipoprotein metabolism, tissue-specific substrate delivery and utilization, and the many aspects of obesity and other metabolic disorders that relate to energy balance, insulin action, and body weight regulation.
757 citations
"Mice lacking ANGPTL8 (Betatrophin) ..." refers background in this paper
...The uptake of TG-fatty acids is controlled by regulating LPL activity in accordance with nutritional status (2)....
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...Am J Physiol Endocrinol Metab 297(2):E271–E288....
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TL;DR: It is shown that the transcription factor, carbohydrate response element-binding protein (ChREBP), is required both for basal and carbohydrate-induced expression of several liver enzymes essential for coordinated control of glucose metabolism, fatty acid, and the synthesis of fatty acids and triglycerides in vivo.
Abstract: The liver provides for long-term energy needs of the body by converting excess carbohydrate into fat for storage. Insulin is one factor that promotes hepatic lipogenesis, but there is increasing evidence that glucose also contributes to the coordinated regulation of carbohydrate and fat metabolism in liver by mechanisms that are independent of insulin. In this study, we show that the transcription factor, carbohydrate response element-binding protein (ChREBP), is required both for basal and carbohydrate-induced expression of several liver enzymes essential for coordinated control of glucose metabolism, fatty acid, and the synthesis of fatty acids and triglycerides in vivo.
714 citations
"Mice lacking ANGPTL8 (Betatrophin) ..." refers background in this paper
...The conversion of carbohydrates to fatty acids is orchestrated by the transcription factors sterol regulatory element binding protein 1 (SREBP1c) and carbohydrate response element binding protein (ChREBP), which promote the transcription of enzymes required for de novo lipogenesis in response to insulin (21, 25)....
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TL;DR: The development of a high-throughput and largely automated process that uses targeting vectors based on bacterial artificial chromosomes (BACs) that permits genetic alteration with nucleotide precision, is not limited by the size of desired deletions, does not depend on isogenicity or on positive–negative selection, and can precisely replace the gene of interest with a reporter that allows for high-resolution localization of target-gene expression.
Abstract: One of the most effective approaches for determining gene function involves engineering mice with mutations or deletions in endogenous genes of interest. Historically, this approach has been limited by the difficulty and time required to generate such mice. We describe the development of a high-throughput and largely automated process, termed VelociGene, that uses targeting vectors based on bacterial artificial chromosomes (BACs). VelociGene permits genetic alteration with nucleotide precision, is not limited by the size of desired deletions, does not depend on isogenicity or on positive-negative selection, and can precisely replace the gene of interest with a reporter that allows for high-resolution localization of target-gene expression. We describe custom genetic alterations for hundreds of genes, corresponding to about 0.5-1.0% of the entire genome. We also provide dozens of informative expression patterns involving cells in the nervous system, immune system, vasculature, skeleton, fat and other tissues.
696 citations
TL;DR: The finding of ANGPTL3 mutations highlights a role for the gene in LDL cholesterol metabolism in humans and shows the usefulness of exome sequencing for identification of novel genetic causes of inherited disorders.
Abstract: We sequenced all protein-coding regions of the genome (the “exome”) in two family members with combined hypolipidemia, marked by extremely low plasma levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. These two participants were compound heterozygotes for two distinct nonsense mutations in ANGPTL3 (encoding the angiopoietin-like 3 protein). ANGPTL3 has been reported to inhibit lipoprotein lipase and endothelial lipase, thereby increasing plasma triglyceride and HDL cholesterol levels in rodents. Our finding of ANGPTL3 mutations highlights a role for the gene in LDL cholesterol metabolism in humans and shows the usefulness of exome sequencing for identification of novel genetic causes of inherited disorders. (Funded by the National Human Genome Research Institute and others.)
644 citations
"Mice lacking ANGPTL8 (Betatrophin) ..." refers background in this paper
...Human homozygotes for loss-of-function mutations in ANGPTL3 have markedly reduced plasma levels of both cholesterol and triglyceride (35)....
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