Mice Lacking Hepatic Lipase Are Lean and Protected against Diet-Induced Obesity and Hepatic Steatosis

Chiu, Harvey K.; Qian, Kun; Ogimoto, Kayoko; Morton, Gregory J.; Wisse, Brent E.; Agrawal, Nalini; McDonald, Thomas O.; Schwartz, Michael W.; Dichek, Helén L.

doi:10.1210/en.2009-1100

Cited by 40 publications

(39 citation statements)

References 31 publications

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“…On the other hand, loss of intracellular TGH/Ces3-lipase which, by contrary, reduces blood lipids and improves glucose tolerance, ameliorated hepatic lipid deposition (Wei et al 2010). Surprisingly, a previous study reported decreased BW gain and reduced hepatic steatosis in HLdeficient mice (Chiu et al 2010). These seemingly discrepancy between these later results and the findings of the present study, might be related to the different dietary regimens used in both studies.…”

Section: Discussioncontrasting

confidence: 93%

Hepatic lipase deficiency produces glucose intolerance, inflammation and hepatic steatosis

Andrés‐Blasco¹,

Herrero-Cervera²,

Vinué³

et al. 2015

Journal of Endocrinology

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Metabolic syndrome and type 2 diabetes mellitus constitute a major problem to global health, and their incidence is increasing at an alarming rate. Non-alcoholic fatty liver disease, which affects up to 90% of obese people and nearly 70% of the overweight, is commonly associated with MetS characteristics such as obesity, insulin resistance, hypertension and dyslipidemia. In the present study, we demonstrate that hepatic lipase (HL)-inactivation in mice fed with a high-fat, high-cholesterol diet produced dyslipidemia including hypercholesterolemia, hypertriglyceridemia and increased non-esterified fatty acid levels. These changes were accompanied by glucose intolerance, pancreatic and hepatic inflammation and steatosis. In addition, compared with WT mice, HL K/K mice exhibited enhanced circulating MCP1 levels, monocytosis and higher percentage of CD4CTh17C cells. Consistent with increased inflammation, livers from HL K/K mice had augmented activation of the stress SAPK/JNK-and p38-pathways compared with the activation levels of the kinases in livers from WT mice. Analysis of HL K/K and WT mice fed regular chow diet showed dyslipidemia and glucose intolerance in HL K/K mice without any other changes in inflammation or hepatic steatosis. Altogether, these results indicate that dyslipidemia induced by HL-deficiency in combination with a high-fat, high-cholesterol diet promotes hepatic steatosis and inflammation in mice which are, at least in part, mediated by the activation of the stress SAPK/JNK-and p38-pathways. Future studies are warranted to asses the viability of therapeutic strategies based on the modulation of these kinases to reduce hepatic steatosis associated to lipase dysfunction.

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Section: Discussioncontrasting

confidence: 93%

Hepatic lipase deficiency produces glucose intolerance, inflammation and hepatic steatosis

Andrés‐Blasco¹,

Herrero-Cervera²,

Vinué³

et al. 2015

Journal of Endocrinology

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“…The increased energy expenditure we have observed in fat-fed WT mice measured by indirect calorimetry has been reported in other studies [43,44]. This increase was not observed in Prkce −/− mice after 1 week of fat feeding, which is in agreement with the increased hepatic lipid accumulation in these animals at this time.…”

Section: Discussionsupporting

confidence: 92%

Time-dependent effects of Prkce deletion on glucose homeostasis and hepatic lipid metabolism on dietary lipid oversupply in mice

et al. 2011

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Aims/hypothesis We examined the time-dependent effects of deletion of the gene encoding protein kinase C epsilon (Prkce) on glucose homeostasis, insulin secretion and hepatic lipid metabolism in fat-fed mice. Methods Prkce −/− and wild-type (WT) mice were fed a high-fat diet for 1 to 16 weeks and subjected to i.p. glucose tolerance tests (ipGTT) and indirect calorimetry. We also investigated gene expression and protein levels by RT-PCR, quantitative protein profiling (isobaric tag for relative and absolute quantification; iTRAQ) and immunoblotting. Lipid levels, mitochondrial oxidative capacity and lipid metabolism were assessed in liver and primary hepatocytes.Results While fat-fed WT mice became glucose intolerant after 1 week, Prkce −/− mice exhibited normal glucose and insulin levels. iTRAQ suggested differences in lipid metabolism and oxidative phosphorylation between fat-fed WT and Prkce −/− animals. Liver triacylglycerols were increased in fat-fed Prkce −/− mice, resulting from altered lipid partitioning which promoted esterification of fatty acids in hepatocytes. In WT mice, fat feeding elevated oxygen consumption in vivo and in isolated liver mitochondria, but these increases were not seen in Prkce −/− mice. Prkce −/− hepatocytes also exhibited reduced production of reactive oxygen species (ROS) in the presence of palmitate. After 16 weeks of fat feeding, however, the improved glucose tolerance in fat-fed Prkce −/− mice was instead associated with increased insulin secretion during ipGTT, as we have previously reported. Conclusions/interpretation Prkce deletion ameliorates dietinduced glucose intolerance via two temporally distinct phenotypes. Protection against insulin resistance is associated with changes in hepatic lipid partitioning, which may reduce the acute inhibitory effects of fatty acid catabolism, such as ROS generation. In the longer term, enhancement of glucose-stimulated insulin secretion prevails.

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“…46 The positive correlation of FTO and PGC1a expression seems to prove that FTO encodes a 2-oxoglutarate-dependent nucleic acid demethylase. 29 As STAT3 and HL are two key genes for glucose and fat metabolism, 47,48 their interaction with FTO overexpression suggests that FTO probably regulates food intake, glucose and fat metabolism through the STAT3 and HL pathways. FTO also increased the expression of GHSR, AMPKb, IGF1R, Leptin-R and PPARa, but these effects are less obvious and are not significant (P40.05).…”

Section: Discussionmentioning

confidence: 99%

Variation in sequence and expression of the avian FTO, and association with glucose metabolism, body weight, fatness and body composition in chickens

et al. 2011

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OBJECTIVE:The fat mass and obesity-associated gene (FTO), a crucial gene that affects human obesity and metabolism, has been widely studied in mammals but remains poorly characterized in birds. We aimed to identify variant FTO transcripts in domestic avian species, and to characterize the expression and biological functions of FTO in chickens. METHODS: Variant FTO transcripts and their expression in birds were investigated using RACE and real-time quantitative reverse transcriptase-PCR technology. The effects of FTO on glucose metabolism, growth and body composition were determined by fasting and various diet treatments, as well as association analysis in a F 2 resource population. The function of cFTO1 was further studied by overexpression in chick embryo fibroblast (CEF) cells. RESULTS: Variant FTO transcripts were identified in chicken (cFTO1 to cFTO4), duck (dFTO1, dFTO2 and dFTO4) and goose (gFTO1, gFTO2 and gFTO5). In the chicken, the complete transcript (cFTO1) was predominantly expressed in the leg muscle, pituitary, hypothalamus and cerebellum. Fasting increased both cFTO1 and PGC1a gene expression in the cerebrum, liver, breast muscle and subcutaneous fat, but decreased expression in the pituitary and anterior hypothalamus. In all tested tissues in chickens, a high-glucose diet markedly increased cFTO1 and PGC1a expression. Feeding a high-fat diet increased both cFTO1 and PGC1a expression, except in the pituitary. Overexpression of cFTO1 in CEF cells significantly increased the expression of PGC1a (2.5-fold), STAT3 (2.2-fold) and HL (1.5-fold), a cluster of genes related to energy metabolism. A total of 65 single nucleotide polymorphisms (SNPs) were identified in chicken FTO, and 18 tested SNPs were significantly associated with traits of body weight, body composition and fatness. CONCLUSIONS: These data collectively indicate that FTO is related to glucose metabolism, body weight, fatness and body composition in birds, thus expanding knowledge of FTO function to non-mammalian species. INTRODUCTIONThe epidemic of human obesity, with its associated high risk for many metabolic diseases, has attracted much attention in recent years. The fat mass and obesity-associated gene (FTO) was recently identified as an obesity candidate gene by three largescale and independent genome-wide association studies, which strongly associated several single nucleotide polymorphisms (SNPs) of FTO with obesity-related traits, including body mass index, hip circumference and body weight. 1 --3 Significant associations between FTO and obesity were independently replicated in many other studies of different populations, including Korean, 4 Japanese, 5 18,20 --22 In mice, FTO deficiency caused postnatal growth retardation and a significant reduction in adipose tissue and lean body mass, 23 and FTO deletion resulted in lesser postnatal growth and lower serum IGF-1 levels. 24 Another mouse model with a missense mutation in FTO maintained linear growth but developed a lean phenotype. 25 Overexpression of FTO leads to a dose-depe...

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Mice Lacking Hepatic Lipase Are Lean and Protected against Diet-Induced Obesity and Hepatic Steatosis

Cited by 40 publications

References 31 publications

Hepatic lipase deficiency produces glucose intolerance, inflammation and hepatic steatosis

Hepatic lipase deficiency produces glucose intolerance, inflammation and hepatic steatosis

Time-dependent effects of Prkce deletion on glucose homeostasis and hepatic lipid metabolism on dietary lipid oversupply in mice

Variation in sequence and expression of the avian FTO, and association with glucose metabolism, body weight, fatness and body composition in chickens

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