Markers of de novo lipogenesis in adipose tissue: associations with small adipocytes and insulin sensitivity in humans

Abstract Variations in body fat (BF) among pigs can be associated with differences in insulin sensitivity given the insulin anabolic effect in lipid synthesis. The study objectives were to characterize this association and compare the relative mRNA abundance of genes associated with insulin resistance and de novo lipogenesis in the adipose tissue of fat and lean pigs. Thirty 95 kg pigs, catheterized in the jugular vein, received an oral dose of 1.75 g glucose/kg of BW after 18 hours of fasting. Blood samples were collected at -20, -10, 5, 10, 15, 20, 25, 30, 45, 60, 90, 120, 150, 180, 210, 240, 300 and 360 minutes following glucose ingestion. Insulin sensitivity indexes were calculated and analyzed. The BF (%) was estimated by dual X-ray densitometry. The 8 fattest (22 % BF) and the 8 leanest pigs (17.2 % BF) were used to determine the relative mRNA abundance of studied genes using real-time qPCR analyses. Insulin sensitivity was determined using QUICKI and Matsuda indexes, respectively, and their association with body fat was studied with Spearman correlations. Differences in gene expression and insulin sensitivity between fat and lean pigs were studied with a one-way ANOVA. The QUICKI and Matsuda indexes negatively correlated with BF (r = -0.67 and r = -0.59; P < 0.001). Fat pigs had reduced insulin sensitivity and higher relative mRNA abundance of lipogenic enzymes (ACACA, ACLY, FASN; P < 0.05) than lean pigs. The higher expression level of glucose-6-phosphate dehydrogenase (G6PD) combined with the trend (P < 0.10) of lower expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ) in fat pigs may explain part of their reduced insulin sensitivity. These results suggest that an increased BF is associated with reduced insulin sensitivity and greater expression of lipogenic enzymes in pig adipose tissue.

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Development of lipogenesis and insulin sensitivity in tissues of the ob/ob mouse

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1981.240.2.e101 ◽

1981 ◽

Vol 240 (2) ◽

pp. E101-E107 ◽

Cited By ~ 4

Author(s):

M. L. Kaplan ◽

G. A. Leveille

Keyword(s):

Adipose Tissue ◽

Fatty Acid ◽

Insulin Sensitivity ◽

Fatty Acid Synthesis ◽

De Novo ◽

Glycogen Synthesis ◽

Lipid Synthesis ◽

Acid Synthesis ◽

De Novo Lipogenesis ◽

Glycerophosphate Dehydrogenase

Lipogenesis and insulin sensitivity are evaluated in adipose tissue, liver, and diaphragm of ob/ob and non-ob/ob mice. In ob/ob mice, hepatic fatty acid synthesis from [U-14C]glucose is elevated by 4 wk of age, and adipose tissue fatty acid synthesis increases at approximately 7 wk. Hepatic activities in ob/ob mice of glucose-6-phosphate dehydrogenase (EC 1.1.1.49), 6-phosphogluconate dehydrogenase (EC 1.1.1.44), malate dehydrogenase (EC 1.1.1.40), and alpha-glycerophosphate dehydrogenase (EC 1.1.1.8) are dramatically increased by 7 wk of age. Diminished insulin-stimulated glycogen synthesis is first noted in the diaphragm of ob/ob mice at 7 wk of age. Insulin-stimulated glycogen synthesis in adipose tissue of ob/ob mice is impaired at 3 wk. At 7 wk, insulin-stimulated fatty acid synthesis in adipose tissue of ob/ob mice is markedly increased. Adipose tissue glyceride-glycerol synthesis continues to increase throughout development, whereas fatty acid synthesis decreases after 7 wk. The data suggest that alterations in lipid synthesis occur very early in the development of ob/ob mouse, prior to expression to overt obesity, at which time a major contribution to lipogenesis is made by the liver. The altered de novo lipogenesis does not precede the reported diminution in energy metabolism.

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The Glucose Sensor ChREBP Links De Novo Lipogenesis to PPARγ Activity and Adipocyte Differentiation

Endocrinology ◽

10.1210/en.2015-1209 ◽

2015 ◽

Vol 156 (11) ◽

pp. 4008-4019 ◽

Cited By ~ 33

Author(s):

Nicole Witte ◽

Matthias Muenzner ◽

Janita Rietscher ◽

Miriam Knauer ◽

Steffi Heidenreich ◽

...

Keyword(s):

Adipose Tissue ◽

Fatty Acid ◽

Insulin Sensitivity ◽

Fatty Acid Synthase ◽

Adipocyte Differentiation ◽

De Novo ◽

Dominant Negative ◽

De Novo Lipogenesis ◽

Dependent Manner ◽

Endogenous Fatty Acid

Reduced de novo lipogenesis in adipose tissue, often observed in obese individuals, is thought to contribute to insulin resistance. Besides trapping excess glucose and providing for triglycerides and energy storage, endogenously synthesized lipids can function as potent signaling molecules. Indeed, several specific lipids and their molecular targets that mediate insulin sensitivity have been recently identified. Here, we report that carbohydrate-response element-binding protein (ChREBP), a transcriptional inducer of glucose use and de novo lipogenesis, controls the activity of the adipogenic master regulator peroxisome proliferator-activated receptor (PPAR)γ. Expression of constitutive-active ChREBP in precursor cells activated endogenous PPARγ and promoted adipocyte differentiation. Intriguingly, ChREBP-constitutive-active ChREBP expression induced PPARγ activity in a fatty acid synthase-dependent manner and by trans-activating the PPARγ ligand-binding domain. Reducing endogenous ChREBP activity by either small interfering RNA-mediated depletion, exposure to low-glucose concentrations, or expressing a dominant-negative ChREBP impaired differentiation. In adipocytes, ChREBP regulated the expression of PPARγ target genes, in particular those involved in thermogenesis, similar to synthetic PPARγ ligands. In summary, our data suggest that ChREBP controls the generation of endogenous fatty acid species that activate PPARγ. Thus, increasing ChREBP activity in adipose tissue by therapeutic interventions may promote insulin sensitivity through PPARγ.

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Adipose tissue regulates insulin sensitivity: role of adipogenesis, de novo lipogenesis and novel lipids

Journal of Internal Medicine ◽

10.1111/joim.12540 ◽

2016 ◽

Vol 280 (5) ◽

pp. 465-475 ◽

Cited By ~ 119

Author(s):

U. Smith ◽

B. B. Kahn

Keyword(s):

Adipose Tissue ◽

Insulin Sensitivity ◽

De Novo ◽

De Novo Lipogenesis

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Adipose tissue triglyceride turnover, de novo lipogenesis, and cell proliferation in humans measured with 2H2O

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00093.2003 ◽

2004 ◽

Vol 286 (4) ◽

pp. E577-E588 ◽

Cited By ~ 206

Author(s):

A. Strawford ◽

F. Antelo ◽

M. Christiansen ◽

M. K. Hellerstein

Keyword(s):

Cell Proliferation ◽

Adipose Tissue ◽

Half Life ◽

De Novo ◽

Human Subjects ◽

De Novo Lipogenesis ◽

Gas Chromatography Mass Spectrometry ◽

Distribution Analysis ◽

Mass Isotopomer Distribution Analysis

The turnover of adipose tissue components (lipids and cells) and the pathways of adipose lipid deposition have been difficult to measure in humans. We apply here a 2H2O long-term labeling technique for concurrent measurement of adipose-triglyceride (TG) turnover, cell (DNA) proliferation, and de novo lipogenesis (DNL). Healthy subjects drank 2H2O (70 ml/day) for 5-9 wk. Subcutaneous adipose tissue aspirates were taken (gluteal, thigh, and flank depots). Deuterium incorporation into TG glycerol (representing all-source TG synthesis), TG palmitate (representing DNL, by mass isotopomer distribution analysis), and DNA (representing cell proliferation) was measured by gas chromatography-mass spectrometry. Subjects tolerated the protocol well, and body 2H2O enrichments were stable. Mean TG-glycerol fractional synthesis was 0.12 (i.e., 12%) with a range of 0.03-0.32 after 5 wk and 0.20 (range 0.08-0.49) after 9 wk (TG half-life 200-270 days). Label decay measurements 5-8 mo after discontinuing 2H2O gave similar turnover estimates. Net lipolysis (TG turnover) was 50-60 g/day. DNL contribution to adipose-TG was 0.04 after 9 wk, representing ∼20% of newly deposited TG. Cell proliferation was 0.10-0.17 after 9 wk (half-life 240-425 days). In summary, long-term 2H2O administration to human subjects allows measurement of the dynamics of adipose tissue components. Turnover of all elements is slow, and DNL contributes ∼20% of new TG.

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Effect of carbohydrate intake on de novo lipogenesis in human adipose tissue

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1987.253.6.e664 ◽

1987 ◽

Vol 253 (6) ◽

pp. E664-E669 ◽

Cited By ~ 5

Author(s):

C. Chascione ◽

D. H. Elwyn ◽

M. Davila ◽

K. M. Gil ◽

J. Askanazi ◽

...

Keyword(s):

Adipose Tissue ◽

De Novo ◽

Acid Synthesis ◽

De Novo Lipogenesis ◽

Whole Body ◽

High Intake ◽

Carbohydrate Diet ◽

Triglyceride Synthesis ◽

High Carbohydrate

Rates of synthesis, from [14C]glucose, of fatty acids (de novo lipogenesis) and glycerol (triglyceride synthesis) were measured in biopsies of adipose tissue from nutritionally depleted patients given low- or high-carbohydrate intravenous nutrition. Simultaneously, energy expenditure and whole-body lipogenesis were measured by indirect calorimetry. Rates of whole-body lipogenesis were zero on the low-carbohydrate diet and averaged 1.6 g.kg-1.day-1 on the high-carbohydrate diet. In vitro rates of triglyceride synthesis increased 3-fold going from the low to the high intake; rates of fatty acid synthesis increased approximately 80-fold. In vitro, lipogenesis accounted for less than 0.1% of triglyceride synthesis on the low intake and 4% on the high intake. On the high-carbohydrate intake, in vitro rates of triglyceride synthesis accounted for 61% of the rates of unidirectional triglyceride synthesis measured by indirect calorimetry. In vitro rates of lipogenesis accounted for 7% of whole-body lipogenesis. Discrepancies between in vitro rates of fatty acid synthesis from glucose, compared with acetate and citrate, as reported by others, suggest that in depleted patients on hypercaloric high-carbohydrate diets, adipose tissue may account for up to 40% of whole-body lipogenesis.

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Metabolic Effects of Oral Phenelzine Treatment on High-Sucrose-Drinking Mice

International Journal of Molecular Sciences ◽

10.3390/ijms19102904 ◽

2018 ◽

Vol 19 (10) ◽

pp. 2904 ◽

Cited By ~ 5

Author(s):

Christian Carpéné ◽

Saioa Gómez-Zorita ◽

Alice Chaplin ◽

Josep Mercader

Keyword(s):

Adipose Tissue ◽

Phosphoenolpyruvate Carboxykinase ◽

De Novo ◽

Uncoupling Protein ◽

De Novo Lipogenesis ◽

Metabolic Effects ◽

Mrna Levels ◽

Brown Adipose ◽

High Sucrose ◽

Sucrose Drinking

Phenelzine has been suggested to have an antiobesity effect by inhibiting de novo lipogenesis, which led us to investigate the metabolic effects of oral chronic phenelzine treatment in high-sucrose-drinking mice. Sucrose-drinking mice presented higher body weight gain and adiposity versus controls. Phenelzine addition did not decrease such parameters, even though fat pad lipid content and weights were not different from controls. In visceral adipocytes, phenelzine did not impair insulin-stimulated de novo lipogenesis and had no effect on lipolysis. However, phenelzine reduced the mRNA levels of glucose transporters 1 and 4 and phosphoenolpyruvate carboxykinase in inguinal white adipose tissue (iWAT), and altered circulating levels of free fatty acids (FFA) and glycerol. Interestingly, glycemia was restored in phenelzine-treated mice, which also had higher insulinaemia. Phenelzine-treated mice presented higher rectal temperature, which was associated to reduced mRNA levels of uncoupling protein 1 in brown adipose tissue. Furthermore, unlike sucrose-drinking mice, hepatic malondialdehyde levels were not altered. In conclusion, although de novo lipogenesis was not inhibited by phenelzine, the data suggest that the ability to re-esterify FFA is impaired in iWAT. Moreover, the effects on glucose homeostasis and oxidative stress suggest that phenelzine could alleviate obesity-related alterations and deserves further investigation in obesity models.

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Pinus Densiflora Bark Extract (PineXol) Decreases Adiposity in Mice by Down-Regulation of Hepatic De Novo Lipogenesis and Adipogenesis in White Adipose Tissue

Journal of Microbiology and Biotechnology ◽

10.4014/jmb.1612.12037 ◽

2017 ◽

Vol 27 (4) ◽

pp. 660-667 ◽

Cited By ~ 5

Author(s):

Hyemyoung Ahn ◽

Gwang-woong Go

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

De Novo ◽

Pinus Densiflora ◽

De Novo Lipogenesis ◽

Bark Extract ◽

Down Regulation

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Risk of diabetes associated with fatty acids in the de novo lipogenesis pathway is independent of insulin sensitivity and response: the Insulin Resistance Atherosclerosis Study (IRAS)

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2019-000691 ◽

2019 ◽

Vol 7 (1) ◽

pp. e000691 ◽

Cited By ~ 3

Author(s):

Waqas Qureshi ◽

Ingrid D Santaren ◽

Anthony J Hanley ◽

Steven M Watkins ◽

Carlos Lorenzo ◽

...

Keyword(s):

Type 2 Diabetes ◽

Fatty Acids ◽

Insulin Sensitivity ◽

Palmitic Acid ◽

De Novo ◽

De Novo Lipogenesis ◽

Diabetes Incidence ◽

Incident Type ◽

Insulin Resistance Atherosclerosis Study

ObjectiveTo examine the associations of fatty acids in the de novo lipogenesis (DNL) pathway, specifically myristic acid (14:0), palmitic acid (16:0),cis-palmitoleic acid (c16:1 n-7),cis-myristoleic acid (c14:1n5), stearic acid (18:0) andcis-oleic acid (c18:1 n-9), with 5-year risk of type 2 diabetes. We hypothesized that DNL fatty acids are associated with risk of type 2 diabetes independent of insulin sensitivity.Research design and methodsWe evaluated 719 (mean age 55.1±8.5 years, 44.2% men, 42.3% Caucasians) participants from the Insulin Resistance Atherosclerosis Study. Multivariable logistic regression models with and without adjustment of insulin sensitivity were used to assess prospective associations of DNL fatty acids with incident type 2 diabetes.ResultsType 2 diabetes incidence was 20.3% over 5 years. In multivariable regression models, palmitic, palmitoleic, myristic, myristoleic and oleic acids were associated with increased risk of type 2 diabetes (p<0.05). Palmitic acid had the strongest association (OR per standard unit of palmitic acid 1.46; 95% CI 1.23 to 1.76; p<0.001), which remained similar with addition of insulin sensitivity and acute insulin response (AIR) to the model (OR 1.36; 95% CI 1.09 to 1.70, p=0.01). Oleic and palmitoleic acids were also independently associated with incident type 2 diabetes. In multivariable models, ratios of fatty acids corresponding to stearoyl CoA desaturase-1 and Elovl6 enzymatic activity were significantly associated with risk of type 2 diabetes independent of insulin sensitivity and AIR.ConclusionsWe observed associations of DNL fatty acids with type 2 diabetes incidence independent of insulin sensitivity.

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