From a glucocentric to a lipocentric approach towards metabolic syndrome

Mittra, Shivani; Bansal, Vinay S.; Bhatnagar, Pradip K.

doi:10.1016/j.drudis.2008.01.006

Cited by 37 publications

(29 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Skeletal muscle biopsies are needed to determine whether the presence of IFG alters in vivo mitochondrial oxidative capacity in adults with IGT (20,29,42). However, given that in vivo (29,42) and in vitro studies (3) report that chronic hyperglycemia overloads mitochondrial oxidative capacity, it appears plausible that exercising with a background of hyperglycemia impairs skeletal muscle glucose uptake through a metabolic stress/inflammatory-related pathway (36). This hypothesis is consistent with evidence that PGC-1␣ and AMPK expression are lower after exercise in insulin-resistant individuals (13,24,30).…”

Section: Discussionmentioning

confidence: 99%

Insulin sensitivity and metabolic flexibility following exercise training among different obese insulin-resistant phenotypes

Malin

Haus

Solomon

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

Malin SK, Haus JM, Solomon TP, Blaszczak A, Kashyap SR, Kirwan JP. Insulin sensitivity and metabolic flexibility following exercise training among different obese insulin-resistant phenotypes. Am J Physiol Endocrinol Metab 305: E1292-E1298, 2013. First published September 24, 2013; doi:10.1152/ajpendo.00441.2013.-Impaired fasting glucose (IFG) blunts the reversal of impaired glucose tolerance (IGT) after exercise training. Metabolic inflexibility has been implicated in the etiology of insulin resistance; however, the efficacy of exercise on peripheral and hepatic insulin sensitivity or substrate utilization in adults with IFG, IGT, or IFG ϩ IGT is unknown. Twenty-four older (66.7 Ϯ 0.8 yr) obese (34.2 Ϯ 0.9 kg/m 2 ) adults were categorized as IFG (n ϭ 8), IGT (n ϭ 8), or IFG ϩ IGT (n ϭ 8) according to a 75-g oral glucose tolerance test (OGTT). Subjects underwent 12-wk of exercise (60 min/day for 5 days/wk at ϳ85% HRmax) and were instructed to maintain a eucaloric diet. A euglycemic hyperinsulinemic clamp (40 mU·m 2 ·min Ϫ1 ) with [6,6-2 H]glucose was used to determine peripheral and hepatic insulin sensitivity. Nonoxidative glucose disposal and metabolic flexibility [insulin-stimulated respiratory quotient (RQ) minus fasting RQ] were also assessed. Glucose incremental area under the curve (iAUCOGTT) was calculated from the OGTT. Exercise increased clamp-derived peripheral and hepatic insulin sensitivity more in adults with IFG or IGT alone than with IFG ϩ IGT (P Ͻ 0.05). Exercise reduced glucose iAUCOGTT in IGT only (P Ͻ 0.05), and the decrease in glucose iAUCOGTT was inversely correlated with the increase in peripheral but not hepatic insulin sensitivity (P Ͻ 0.01). Increased clamp-derived peripheral insulin sensitivity was also correlated with enhanced metabolic flexibility, reduced fasting RQ, and higher nonoxidative glucose disposal (P Ͻ 0.05). Adults with IFG ϩ IGT had smaller gains in clamp-derived peripheral insulin sensitivity and metabolic flexibility, which was related to blunted improvements in postprandial glucose. Additional work is required to assess the molecular mechanism(s) by which chronic hyperglycemia modifies insulin sensitivity following exercise training. obesity; prediabetes; insulin resistance; cardiometabolic; exercise APPROXIMATELY 79 MILLION ADULTS in the US have impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or both (IFG ϩ IGT) and are collectively referred to as having prediabetes (2). Focusing on adults with IFG, IGT, and IFG ϩ IGT is clinically important since each phenotype has a unique pathology that promotes different degrees of cardiovascular disease risk (8, 31). The exact cause for the difference in disease risk is unclear, but the degree of insulin resistance in skeletal muscle or the liver is a likely candidate. Individuals with IGT [2-h oral glucose tolerance test (OGTT) values between 140 and 199 mg/dl] are typically characterized as having reduced skeletal muscle insulin sensitivity, whereas adults with IFG (fasting glucose 100 -125 mg/dl) generally h...

show abstract

Section: Discussionmentioning

confidence: 99%

Insulin sensitivity and metabolic flexibility following exercise training among different obese insulin-resistant phenotypes

Malin

Haus

Solomon

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

show abstract

“…RNA interference (RNAi) functional screens in Drosophila and mammalian cells have identifi ed several biochemical pathways regulating LD biogenesis and utilization ( 4,5 ). These studies established that the LD compartment is not just a passive sink storing intracellular FAs, but rather, it is a highly regulated, metabolically active organelle with a wide range of functions involving lipid fl ux, protein traffi cking, and interaction with other organelles, including mitochondria ( 4-6 ).…”

Section: Cell Culturementioning

confidence: 99%

“…␤ -oxidation using metabolic radioactive labeling was performed in control or Plin5-YFP cells as described ( 30 ). Cells were seeded in a 24-multiwell dish and exposed to DMEM supplemented with 0.24 mmol/l fatty acidfree albumin (BSA), 0.5 mmol/l L-carnitine, 20 mmol/l HEPES, and [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C] palmitate (1.0 Ci/ml, 0.017 mmol/l) with 5 mmol/l glucose ( 30 ). After CO 2 trapping, the incubation media were transferred to new tubes and assayed for labeled ␤ -oxidation regulator, along with humidifi cation and an objective heater.…”

Section: ␤ -Oxidation Measurementsmentioning

confidence: 99%

Perilipin 5, a lipid droplet-associated protein, provides physical and metabolic linkage to mitochondria

Wang

Sreenivasan

et al. 2011

Journal of Lipid Research

393

343

View full text Add to dashboard Cite

Cellular energy homeostasis of oxidative tissue relies on a critical balance between fatty acid (FA) uptake from the environment and consumption by mitochondria oxidation. These processes are controlled by complex regulatory mechanisms that ensure energy needs are met while preventing buildup of toxic lipid intermediates and/or oxidized lipids. Transient formation of lipid droplets (LD) may protect mitochondria from lipotoxicity in physiological conditions such as fasting. However, with chronic excess FA levels as observed in obesity, LDs not only cease to be protective but may also contribute to pathology ( 1 ). Distinct features of cardiomyopathy appear in obese and diabetic type 2 patients, including accumulation of lipid droplets and long chain fatty acyl compounds (ceramides, acyl carnitines, and CoAs) in cardiomyocytes, which are Abstract Maintaining cellular lipid homeostasis is crucial to oxidative tissues, and it becomes compromised in obesity. Lipid droplets (LD) play a central role in lipid homeostasis by mediating fatty acid (FA) storage in the form of triglyceride, thereby lowering intracellular levels of lipids that mediate cellular lipotoxicity. LDs and mitochondria have interconnected functions, and anecdotal evidence suggests they physically interact. However, the mechanisms of interaction have not been identifi ed. Perilipins are LD-scaffolding proteins and potential candidates to play a role in their interaction with mitochondria. We examined the contribution of LD perilipin composition to the physical and metabolic interactions between LD and mitochondria using multiple techniques: confocal imaging, electron microscopy (EM), and lipid storage and utilization measurements. Using neonatal cardiomyocytes, reconstituted cell culture models, and rodent heart tissues, we found that perilipin 5 (Plin5) recruits mitochondria to the LD surface through a C-terminal region. Compared with control cells, Plin5-expressing cells show decreased LD hydrolysis, decreased palmitate ␤ -oxidation, and increased palmitate incorporation into triglycerides in basal conditions, whereas in stimulated conditions, LD hydrolysis inhibition is lifted and FA released for ␤ -oxidation. These results suggest that Plin5 regulates oxidative LD hydrolysis and controls local FA fl ux to protect mitochondria against excessive exposure to FA Abbreviations: AA, amino acid; ADFP, adipose differentiationrelated protein; ASM, acid-soluble metabolite; CHO-K1, Chinese hamster ovary; EM, electron microscopy; ER, endoplasmic reticulum; LD, lipid droplet; OCR, oxygen consumption rate; Plin1, perilipin 1, perilipin A; Plin2, perilipin 2, ADFP; Plin5, perilipin 5, Lipid Storage Droplet Protein 5; PPAR ␣ , peroxisome proliferator-activated receptor ␣ ; RNAi, RNA interference; TIP47, tail interacting protein. This work was supported by American Diabetes Association Career Development Award 1-05-CD-17 (C.S.); by National Institutes of Health Grant 1RO1-DK-075017 (C.S.); by American Heart Association Grant-in-Aid 11GRNT7600027 (C.S.); by the Ger...

show abstract

“…Some consider an initial insulin resistant state progressing to the other components, while others are of view that obesity is the main initiator of the syndrome [6]. More recently, the chronic low-grade inflammatory condition that often accompanies the metabolic syndrome has been implicated as a major factor both in the installation of the metabolic syndrome and its associated pathophysiological consequences [7].…”

mentioning

confidence: 99%

Inflammation and the Metabolic Syndrome

Sharma

2011

Ind J Clin Biochem

View full text Add to dashboard Cite

From a glucocentric to a lipocentric approach towards metabolic syndrome

Cited by 37 publications

References 74 publications

Insulin sensitivity and metabolic flexibility following exercise training among different obese insulin-resistant phenotypes

Insulin sensitivity and metabolic flexibility following exercise training among different obese insulin-resistant phenotypes

Perilipin 5, a lipid droplet-associated protein, provides physical and metabolic linkage to mitochondria

Inflammation and the Metabolic Syndrome

Contact Info

Product

Resources

About