Pharmacological glycerol-3-phosphate acyltransferase inhibition decreases food intake and adiposity and increases insulin sensitivity in diet-induced obesity

Kuhajda, Francis P.; Tu, Yajun; Han, Wan Fang; Medghalchi, Susan M.; Meskini, Rajaâ El; Landree, Leslie E.; Peterson, Jonathan M.; Daniels, Khadija; Wong, Kody; Wydysh, Edward A.; Townsend, Craig A.; Ronnett, Gabriele V.

doi:10.1152/ajpregu.00147.2011

Cited by 42 publications

(52 citation statements)

References 55 publications

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“…These results raise questions about whether GPAT1 inhibitors are potential therapeutic targets to improve fatty acid metabolism in the adipose tissue of obese patients; however, it is also possible that GPAT1 inhibition would lead to harmful ectopic fat accumulation. Of note, in a diet-induced obesity mouse model, administration of the small-molecule GPAT inhibitor FSG67 leads to 1) decreased adiposity; 2) increased fatty acid oxidation; and 3) reduced dietary intake (19). We speculate that effects on appetite overwhelm any negative effects of inhibition of GPAT or GPAT1 in adipose tissue.…”

mentioning

confidence: 88%

Sex and depot differences in ex vivo adipose tissue fatty acid storage and glycerol-3-phosphate acyltransferase activity

Morgan‐Bathke

Chen

Oberschneider

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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Morgan-Bathke M, Chen L, Oberschneider E, Harteneck D, Jensen MD. Sex and depot differences in ex vivo adipose tissue fatty acid storage and glycerol-3-phosphate acyltransferase activity. Am J Physiol Endocrinol Metab 308: E830 -E846, 2015. First published March 3, 2015 doi:10.1152/ajpendo.00424.2014.-Adipose tissue fatty acid storage varies according to sex, adipose tissue depot, and degree of fat gain. However, the mechanism(s) for these variations is not completely understood. We examined whether differences in adipose tissue glycerol-3-phosphate acyltransferase (GPAT) might play a role in these variations. We optimized an enzyme activity assay for total GPAT and GPAT1 activity in human adipose tissue and measured GPAT activity. Omental and subcutaneous adipose tissue was collected from obese and nonobese adults for measures of GPAT and GPAT1 activities, ex vivo palmitate storage, acyl-CoA synthetase (ACS) and diacylglycerol-acyltransferase (DGAT) activities, and CD36 protein. Total GPAT and GPAT1 activities decreased as a function of adipocyte size in both omental (r ϭ Ϫ0.71, P ϭ 0.003) and subcutaneous (r ϭ Ϫ0.58, P ϭ 0.04) fat. The relative contribution of GPAT1 to total GPAT activity increased as a function of adipocyte size, accounting for up to 60% of GPAT activity in those with the largest adipocytes. We found strong, positive correlations between ACS, GPAT, and DGAT activities for both sexes and depots (r values 0.58 -0.91) and between these storage factors and palmitate storage rates into TAG (r values 0.55-0.90). We conclude that: 1) total GPAT activity decreases as a function of adipocyte size; 2) GPAT1 can account for over half of adipose GPAT activity in hypertrophic obesity; and 3) ACS, GPAT, and DGAT are coordinately regulated. omental fat; subcutaneous fat; fat distribution; glycerol-3-phosphate acyltransferase 1 BODY FAT DISTRIBUTION PLAYS an important role in the development of the comorbidities associated with obesity. In general, adults with greater amounts of visceral fat have more risk for chronic disease than those with a lesser proportion of visceral fat (14). Although regional balances of fatty acids (uptake vs. release) should determine whether one depot expands at the expense of another, interindividual differences in regional lipolysis (8,13,24) and meal fat storage (21, 26, 31) do not appear to explain differences in body fat distribution. We found that direct free fatty acid (FFA) storage rates in subcutaneous fat are greater in women than men and that the sex-specific variations in direct FFA storage into adipocyte triacylglycerol (TAG) are consistent with body fat distribution patterns (16,18,28). On average, the protein content (CD36 and fatty acid transport protein 1) and enzyme activity [acyl-

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confidence: 88%

Sex and depot differences in ex vivo adipose tissue fatty acid storage and glycerol-3-phosphate acyltransferase activity

Morgan‐Bathke

Chen

Oberschneider

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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“…To monitor lipid synthesis in the cells, FASN (a key enzyme in the synthesis of fatty acids from acetyl-CoA) was employed [22], in addition to GPAM, which catalyzes the first rate-limiting step in the synthesis of glycerolipids [23], and analyzed by mRNA expression. Both FASN and GPAM mRNA levels combined with the generation of lipid vesicles of brown adipocytes incubated with fructose and glucose increased with similar kinetics compared to cells incubated with glucose only.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Culture of Human Brown Adipocytes: Effects of Fructose

Huber¹,

Wödl²,

Robubi³

et al. 2016

LSMR

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Abstract-Brown adipocytes can be distinguished from their white counterparts by markers such as UCP-1 or P2RX5. This study cultured brown human adipocytes in growth media containing 0.1 g/L and 1 g/L fructose in addition to glucose and monitored the cell growth. Unexpectedly, the cultured cells co-expressed markers for white adipocytes (ASC-1) and markers for brown adipocytes (P2RX5). Cells developed multilocular lipid vesicles and exhibited similar kinetics of mRNAs involved in lipogenesis with and without fructose. Excessive amounts of fructose induce negative effects on insulin sensitivity, blood pressure, and liver metabolism. These adverse outcomes were attributed to disturbances in key metabolic pathways in the liver. However, possible consequences of high fructose levels when in direct contact with human white adipocytes in vivo have been considered. No such data existed on the effects of fructose on human brown adipocytes. Results indicate that in addition to toxic effects on liver cells, human white and brown adipocytes consume extra fructose and generate new lipid vesicles, further deregulating energy homeostasis.

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“…19 Recently, the inhibition of lipogenesis was shown to increase fatty acid oxidation. 20,33 Carnitine palmitoyltransferase-1 (CPT-1), the rate-limiting enzyme of the mitochondrial fatty acid b-oxidation, and GPAT1 are both located on the outer mitochondrial membrane and compete for long-chain acyl-CoAs as their substrate. Genetic or pharmacological GPAT inhibition resulted in an increase in oxidation because the acyl-CoA substrates were partitioned toward CPT-1 for b-oxidation rather than the TAG synthetic pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, a couple of GPAT inhibitors have been reported. 20,21 However, the pharmacological validation of their use in cells and animal models remains to be examined.…”

Section: Introductionmentioning

confidence: 99%

Aralia cordata Inhibits Triacylglycerol Biosynthesis in HepG2 Cells

Kim

Lee²,

Seo³

et al. 2013

Journal of Medicinal Food

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Glycerol-3-phosphate acyltransferase (GPAT) catalyzes the first committed step in triacylglycerol (TAG) and phospholipid biosynthesis, and has been considered as one of the drug targets for treating hepatic steatosis, insulin resistance, and other metabolic disorders. The aim of this study was to investigate the GPAT inhibitors from natural products and to evaluate their effects. The methanol extract of Aralia cordata roots showed a strong inhibitory effect on the human GPAT1 activity. A further bioactivity-guided approach led to the isolation of ent-pimara-8(14),15-dien-19-oic acid, (PA), one of the major compounds of A. cordata, which suppressed the GPAT1 activity with IC50 value of 60.5 μM. PA markedly reduced de novo lysophosphatidic acid synthesis through inhibition of GPAT activity and therefore significantly decreased synthesis of TAG in the HepG2 cells. These results suggest that PA as well as A. cordata root extract could be beneficial in controlling lipid metabolism.

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Pharmacological glycerol-3-phosphate acyltransferase inhibition decreases food intake and adiposity and increases insulin sensitivity in diet-induced obesity

Cited by 42 publications

References 55 publications

Sex and depot differences in ex vivo adipose tissue fatty acid storage and glycerol-3-phosphate acyltransferase activity

Sex and depot differences in ex vivo adipose tissue fatty acid storage and glycerol-3-phosphate acyltransferase activity

In Vitro Culture of Human Brown Adipocytes: Effects of Fructose

Aralia cordata Inhibits Triacylglycerol Biosynthesis in HepG2 Cells

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