Loss of regulation of lipogenesis in the Zucker diabetic (ZDF) rat

2000 ◽  
Vol 279 (2) ◽  
pp. E425-E432 ◽  
Author(s):  
W.-N. Paul Lee ◽  
Sara Bassilian ◽  
Shu Lim ◽  
Laszlo G. Boros
Keyword(s):  
High Fat Diet ◽  
Leptin Receptor ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Chain Elongation ◽  
Deuterated Water ◽  
High Fat ◽  
Macronutrient Composition ◽  
Zdf Rat

We present here a study on the role of leptin in the regulation of lipogenesis by examining the effect of dietary macronutrient composition on lipogenesis in the leptin receptor-defective Zucker diabetic fatty rat (ZDF) and its lean litter mate (ZL). Animals were pair fed two isocaloric diets differing in their fat-to-carbohydrate ratio providing 10 and 30% energy as fat. Lipogenesis was measured in the rats using deuterated water and isotopomer analysis. From the deuterium incorporation into plasma palmitate, stearate, and oleate, we determined de novo synthesis of palmitate and synthesis of stearate by chain elongation and of oleate by desaturation. Because the macronutrient composition and the caloric density were controlled, changes in de novo lipogenesis under these dietary conditions represent adaptation to changes in the fat-to-carbohydrate ratio of the diet. De novo lipogenesis was normally suppressed in response to the high-fat diet in the ZL rat to maintain a relatively constant amount of lipids transported. The ZDF rat had a higher rate of lipogenesis, which was not suppressed by the high-fat diet. The results suggest an important hormonal role of leptin in the feedback regulation of lipogenesis.

Loss of regulation of lipogenesis in the Zucker diabetic rat. II. Changes in stearate and oleate synthesis

2002 ◽  
Vol 282 (3) ◽  
pp. E507-E513 ◽  
Author(s):  
Sara Bassilian ◽  
Syed Ahmed ◽  
Shu K. Lim ◽  
Laszlo G. Boros ◽  
Catherine S. Mao ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Dietary Fat ◽  
High Fat Diet ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Chain Elongation ◽  
High Fat ◽  
Zdf Rat

De novo lipogenesis and dietary fat uptake are two major sources of fatty acid deposits in fat of obese animals. To determine the relative contribution of fatty acids from these two sources in obesity, we have determined the distribution of c16 and c18 fatty acids of triglycerides in plasma, liver, and epididymal fat pad of Zucker diabetic fatty (ZDF) rats and their lean littermates (ZL) under two isocaloric dietary fat conditions. Lipogenesis was also determined using the deuterated water method. Conversion of palmitate to stearate and stearate to oleate was calculated from the deuterium incorporation by use of the tracer dilution principle. In the ZL rat, lipogenesis was suppressed from 70 to 24%, conversion of palmitate to stearate from 86 to 78%, and conversion of stearate to oleate from 56 to 7% in response to an increase in the dietary fat-to-carbohydrate ratio. The results suggest that suppression of fatty acid synthase and stearoyl-CoA desaturase activities is a normal adaptive mechanism to a high-fat diet. In contrast, de novo lipogenesis, chain elongation, and desaturation were not suppressed by dietary fat in the ZDF rat. The lack of ability to adapt to a high-fat diet resulted in a higher plasma triglyceride concentration and excessive fat accumulation from both diet and de novo synthesis in the ZDF rat.

Role of human liver lipogenesis and reesterification in triglycerides secretion and in FFA reesterification

1998 ◽  
Vol 274 (2) ◽  
pp. E321-E327 ◽  
Author(s):  
Frederique Diraison ◽  
Michel Beylot
Keyword(s):  
Turnover Rate ◽  
De Novo ◽  
Plasma Free Fatty Acid ◽  
Normal Subjects ◽  
De Novo Lipogenesis ◽  
Deuterated Water ◽  
Extrahepatic Tissues ◽  
Almost All ◽  
State 1

To measure 1) the contribution of hepatic de novo lipogenesis (DNL) and plasma free fatty acid (FFA) reesterification to plasma triglyceride (TG) secretion, and 2) the role of oxidation and hepatic and extrahepatic reesterification in FFA utilization, five normal subjects drank deuterated water and were infused (postabsorptive state) with [1-13C]palmitate and [1,2,3-2H5]glycerol. Total lipid oxidation (Lox) was measured by indirect calorimetry. FFA oxidation (2.76 ± 0.65 μmol ⋅ kg−1 ⋅ min−1) accounted for 45% of FFA turnover rate (Rt) (1.04 μmol ⋅ kg−1 ⋅ min−1) and 91% of Lox; FFA reesterification was 3.27 ± 0.54 μmol ⋅ kg−1 ⋅ min−1. Fractional and absolute TG Rt were 0.21 ± 0.02 h−1 and 0.11 ± 0.05 μmol ⋅ kg−1 ⋅ min−1. DNL accounted for 3.9 ± 0.9% of TG secretion, and hepatic FFA reesterification accounted for 49.4 ± 5.7%; this last process represented a utilization of FFA of 0.16 ± 0.02 μmol ⋅ kg−1 ⋅ min−1. We conclude that, in the postabsorptive state, 1) DNL and FFA reesterification account for only 50–55% of TG secretion, the remaining presumably being provided by stored lipids or lipoproteins taken up by liver, 2) most reesterification occurs in extrahepatic tissues, and 3) oxidation and reesterification each contribute about one-half to FFA utilization; FFA oxidation accounts for almost all Lox.

scholarly journals A high-fat diet suppresses de novo lipogenesis and desaturation but not elongation and triglyceride synthesis in mice

2014 ◽  
Vol 55 (12) ◽  
pp. 2541-2553 ◽  
Author(s):  
Joao A. G. Duarte ◽  
Filipa Carvalho ◽  
Mackenzie Pearson ◽  
Jay D. Horton ◽  
Jeffrey D. Browning ◽  
...  
Keyword(s):  
High Fat Diet ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
High Fat ◽  
Triglyceride Synthesis

scholarly journals Polyunsaturated Fatty Acids Stimulate De novo Lipogenesis and Improve Glucose Homeostasis during Refeeding with High Fat Diet

2017 ◽  
Vol 8 ◽  
Author(s):  
Raffaella Crescenzo ◽  
Arianna Mazzoli ◽  
Rosa Cancelliere ◽  
Francesca Bianco ◽  
Antonia Giacco ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Polyunsaturated Fatty Acids ◽  
Glucose Homeostasis ◽  
High Fat Diet ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
High Fat

scholarly journals Niacin Ameliorates Hepatic Steatosis by Inhibiting De Novo Lipogenesis Via a GPR109A-Mediated PKC–ERK1/2–AMPK Signaling Pathway in C57BL/6 Mice Fed a High-Fat Diet

2019 ◽  
Vol 150 (4) ◽  
pp. 672-684 ◽  
Author(s):  
Lingyan Ye ◽  
Zheng Cao ◽  
Xiangru Lai ◽  
Ying Shi ◽  
Naiming Zhou
Keyword(s):  
Liver Disease ◽  
Protein Kinase ◽  
Fatty Liver ◽  
Signaling Pathway ◽  
Lipid Accumulation ◽  
High Fat Diet ◽  
Hepg2 Cells ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
High Fat

ABSTRACT Background Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. Hepatic de novo lipogenesis (DNL) has been suggested to contribute to the pathogenesis of NAFLD. Recent studies have demonstrated that niacin (NA) modulates hepatic DNL through GPR109A. However, the underlying mechanism remains largely unknown. Objectives This study aims to elucidate the potential molecular mechanism by which GPR109A inhibits hepatic DNL. Methods C57BL/6 wild-type (WT) and Gpr109a knockout (KO) mice (male, 5 wk old) were fed a high-fat diet (60% energy from fat) firstly for 6 wk to generate a diet-induced obese model. Subsequently, they were randomly divided into 4 groups for the next 8–9 wk: WT mice with oral water [WT + vehile (VE)], WT mice with oral NA (50 mM, dissolved in water) (WT + NA), KO mice with oral water (KO + VE), and KO mice with oral NA (50 mM) (KO + NA). Mechanisms were examined in HepG2 cells. Body composition, liver histology, biomarkers of hepatic function, lipid accumulation, and lipid synthesis signals in HepG2 cells were measured. Results Upon activation, GPR109A apparently protected against obesity and hepatic steatosis (P < 0.05). The concentrations of hepatic Tnf-α in the WT + NA group were about 50% of those in the WT + VE group (P < 0.05). The activities of serum alanine transaminase and aspartate transaminase were 26.7% and 53.5% lower in the WT + NA group than in the WT + VE group, respectively (P < 0.05). In HepG2 cells, activation of GPR109A resulted in remarkable inhibition of oleic acid–induced lipid accumulation via a protein kinase C–extracellular signal-regulated kinase-1/2–AMP-activated protein kinase signaling pathway. Conclusions NA inhibits hepatic lipogenesis in C57BL/6 mice through a GPR109A-mediated signaling pathway, consistent with the mechanistic studies in HepG2 cells, suggesting its potential for treatment of NAFLD and other fatty liver diseases.

scholarly journals The Dualistic Effect of COX-2-Mediated Signaling in Obesity and Insulin Resistance

2019 ◽  
Vol 20 (13) ◽  
pp. 3115 ◽  
Author(s):  
Pei-Chi Chan ◽  
Min-Tser Liao ◽  
Po-Shiuan Hsieh
Keyword(s):  
Insulin Resistance ◽  
High Fat Diet ◽  
De Novo ◽  
Strongly Correlated ◽  
High Fat ◽  
Over Expression ◽  
Diet Induced Obesity ◽  
Key Enzyme ◽  
Cox 2

Obesity and insulin resistance are two major risk factors for the development of metabolic syndrome, type 2 diabetes and associated cardiovascular diseases (CVDs). Cyclooxygenase (COX), a rate-limiting enzyme responsible for the biosynthesis of prostaglandins (PGs), exists in two isoforms: COX-1, the constitutive form, and COX-2, mainly the inducible form. COX-2 is the key enzyme in eicosanoid metabolism that converts eicosanoids into a number of PGs, including PGD2, PGE2, PGF2α, and prostacyclin (PGI2), all of which exert diverse hormone-like effects via autocrine or paracrine mechanisms. The COX-2 gene and immunoreactive proteins have been documented to be highly expressed and elevated in adipose tissue (AT) under morbid obesity conditions. On the other hand, the environmental stress-induced expression and constitutive over-expression of COX-2 have been reported to play distinctive roles under different pathological and physiological conditions; i.e., over-expression of the COX-2 gene in white AT (WAT) has been shown to induce de novo brown AT (BAT) recruitment in WAT and then facilitate systemic energy expenditure to protect mice against high-fat diet-induced obesity. Hepatic COX-2 expression was found to protect against diet-induced steatosis, obesity, and insulin resistance. However, COX-2 activation in the epidydimal AT is strongly correlated with the development of AT inflammation, insulin resistance, and fatty liver in high-fat-diet-induced obese rats. This review will provide updated information regarding the role of COX-2-derived signals in the regulation of energy metabolism and the pathogenesis of obesity and MS.

scholarly journals Alleviative effect of Ruellia tuberosa L. on NAFLD and hepatic lipid accumulation via modulating hepatic de novo lipogenesis in high‐fat diet plus streptozotocin‐induced diabetic rats

2020 ◽  
Vol 8 (10) ◽  
pp. 5710-5716 ◽  
Author(s):  
Da‐Wei Huang ◽  
Yangming Martin Lo ◽  
Wen‐Chang Chang ◽  
Chia‐Yu Lin ◽  
Jou‐An Chen ◽  
...  
Keyword(s):  
Lipid Accumulation ◽  
High Fat Diet ◽  
De Novo ◽  
Diabetic Rats ◽  
De Novo Lipogenesis ◽  
High Fat ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation

scholarly journals miR-146a regulates insulin sensitivity via NPR3

2020 ◽  
Author(s):  
Julian Roos ◽  
Meike Dahlhaus ◽  
Jan-Bernd Funcke ◽  
Monika Kustermann ◽  
Gudrun Strauss ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
High Fat Diet ◽  
Metabolic Diseases ◽  
De Novo ◽  
Liver Steatosis ◽  
De Novo Lipogenesis ◽  
Loss Of Function ◽  
High Fat

AbstractThe pathogenesis of obesity-related metabolic diseases has been linked to the inflammation of white adipose tissue (WAT), but the molecular interconnections are still not fully understood. MiR-146a controls inflammatory processes by suppressing pro-inflammatory signaling pathways. The aim of this study was to characterize the role of miR-146a in obesity and insulin resistance. MiR-146a−/− mice were subjected to a high-fat diet followed by metabolic tests and WAT transcriptomics. Gain- and loss-of-function studies were performed using human Simpson–Golabi–Behmel syndrome (SGBS) adipocytes. Compared to controls, miR-146a−/− mice gained significantly more body weight on a high-fat diet with increased fat mass and adipocyte hypertrophy. This was accompanied by exacerbated liver steatosis, insulin resistance, and glucose intolerance. Likewise, adipocytes transfected with an inhibitor of miR-146a displayed a decrease in insulin-stimulated glucose uptake, while transfecting miR-146a mimics caused the opposite effect. Natriuretic peptide receptor 3 (NPR3) was identified as a direct target gene of miR-146a in adipocytes and CRISPR/Cas9-mediated knockout of NPR3 increased insulin-stimulated glucose uptake and enhanced de novo lipogenesis. In summary, miR-146a regulates systemic and adipocyte insulin sensitivity via downregulation of NPR3.

scholarly journals Excitatory transmission onto AgRP neurons is regulated by cJun NH2-terminal kinase 3 in response to metabolic stress

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Santiago Vernia ◽  
Caroline Morel ◽  
Joseph C Madara ◽  
Julie Cavanagh-Kyros ◽  
Tamera Barrett ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
High Fat Diet ◽  
Leptin Receptor ◽  
Metabolic Stress ◽  
Homeostatic Regulation ◽  
High Fat ◽  
Jnk Signaling ◽  
Excitatory Transmission ◽  
Jnk Signaling Pathway

The cJun NH2-terminal kinase (JNK) signaling pathway is implicated in the response to metabolic stress. Indeed, it is established that the ubiquitously expressed JNK1 and JNK2 isoforms regulate energy expenditure and insulin resistance. However, the role of the neuron-specific isoform JNK3 is unclear. Here we demonstrate that JNK3 deficiency causes hyperphagia selectively in high fat diet (HFD)-fed mice. JNK3 deficiency in neurons that express the leptin receptor LEPRb was sufficient to cause HFD-dependent hyperphagia. Studies of sub-groups of leptin-responsive neurons demonstrated that JNK3 deficiency in AgRP neurons, but not POMC neurons, was sufficient to cause the hyperphagic response. These effects of JNK3 deficiency were associated with enhanced excitatory signaling by AgRP neurons in HFD-fed mice. JNK3 therefore provides a mechanism that contributes to homeostatic regulation of energy balance in response to metabolic stress.

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