Prohibitin attenuates insulin‐stimulated glucose and fatty acid oxidation in adipose tissue by inhibition of pyruvate carboxylase

Vessal, Mahmood; Mishra, Suresh; Moulik, Sabyasachi; Murphy, Liam

doi:10.1111/j.1742-4658.2005.05090.x

Cited by 55 publications

(57 citation statements)

References 28 publications

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“…26,50 Previously, we have reported that PHB interacts with PC and inhibits insulin-induced glucose and fatty acid oxidation in adipose tissues. 25 However, the relevance of PHB and PC interaction in fatty acid synthesis and glyceroneogenesis remain to be determined. Enhanced lipogenesis in PHB overexpressing 3T3-L1 adipocytes would indicate that a metabolic shift may underlie the molecular mechanism involved in PHB's role in the adipogenesis mediated through PC, in addition to the modulatory effect of PHB on insulin signaling.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we have reported that PHB modulates insulin signaling in a phosphorylation-dependent manner. 23,24 In addition, we have shown that PHB interacts with pyruvate carboxylase (PC), 25 an important enzyme involved in de novo fatty acid synthesis and glyceroneogenesis. 26 Furthermore, PHB has been reported to be involved in Raf activation and to have an important role in MAPK/ERK signaling.…”

Section: Introductionmentioning

confidence: 99%

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Prohibitin has an important role in adipocyte differentiation

Ande

et al. 2011

Int J Obes

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OBJECTIVE: To investigate whether prohibitin (PHB) is a target gene in adipocyte differentiation and modulates insulin-induced adipocyte differentiation. DESIGN: 3T3-L1 preadipocyte overexpressing wild-type PHB and PHB mutant (lacking tyrosine-114 phosphorylation site) with or without insulin. RESULTS: The treatment of 3T3-L1 fibroblasts with insulin or peroxisome proliferator-activated receptor-g agonist resulted in an upregulation of PHB in a dose-and time-dependent manner. An analysis of the PHB promoter sequence revealed the presence of putative insulin-response elements and CCAAT/enhancer-binding protein transcription elements within B1 kb upstream of the translation initiation site. The functional relevance of these sites was determined using reporter gene assay. Surprisingly, PHB was also found to be regulated by leptin. Furthermore, the overexpression of PHB in 3T3-L1 fibroblasts was sufficient to induce adipogenesis. CONCLUSION: In summary, we have identified PHB as an important protein in adipocyte differentiation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prohibitin has an important role in adipocyte differentiation

Ande

et al. 2011

Int J Obes

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“…This is likely an over simplification of the functional role of the prohibitins in the mitochondria. We recently reported that Phb1 is a potent inhibitor of pyruvate carboxylase [44], a mitochondrial enzyme involved in replenishing tricarboxylic acid cycle intermediates [45]. When added to murine adipocytes, Phb1 can be translocated to the mitochondria and can inhibit anaplerosis [44].…”

Section: Prohibitins and Mitochondrial Functionmentioning

confidence: 99%

“…We recently reported that Phb1 is a potent inhibitor of pyruvate carboxylase [44], a mitochondrial enzyme involved in replenishing tricarboxylic acid cycle intermediates [45]. When added to murine adipocytes, Phb1 can be translocated to the mitochondria and can inhibit anaplerosis [44]. It is not clear whether Phb2 shares this activity, nor is it clear whether Phb1 inhibition of pyruvate carboxylase of physiological significance.…”

Section: Prohibitins and Mitochondrial Functionmentioning

confidence: 99%

The Prohibitins: emerging roles in diverse functions

Mishra

Murphy

2006

Journal of Cellular and Molecular Medicine

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221

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Prohibitin 1, (Phb1) has a molecular mass of ~30 kDa and is also known as B-cell receptor associated protein-32 (BAP32), whereas a related protein, prohibitin 2 (Phb2), sometimes referred to as prohibitone [1], B-cell receptor associated protein-37 (BAP37) [2] or repressor of estrogen receptor action (REA) [3] has a mass of ~37 kDa. For the purpose of this review we will use the nomenclature of Phb1 and Phb2. The prohibitin name is derived from an historical perspective and probably only relates to one of the many physiological roles of these proteins. A Phb1 cDNA was first isolated by differential hybridization to RNA from normal versus regenerating rat liver [4] and consequently Phb1 was proposed to be an inhibitor of cellular proliferation, hence the name prohibitin. The corresponding mRNA when microinjected into normal human diploid fibroblasts attenuated DNA synthesis. However it was subsequently shown that this effect was attributable to the 3' untranslated region of the AbstractThe prohibitins, Phb1 and Phb2 are highly conserved proteins in eukaryotic cells that are present in multiple cellular compartments. Initial investigations focused on the role of Phb1 as an inhibitor of cell proliferation hence the original name prohibitin. However both proteins appear to have a diverse range of functions and recent evidence suggests that the prohibitins have very similar but as yet only partially understood functions. In addition to their role as chaperone proteins in the mitochondria, and their ability to target to lipid rafts, their is now compelling evidence that both prohibitins are localized in the nucleus and can modulate transcriptional activity by interacting with various transcription factors, including the steroid hormone receptors, either directly or indirectly. In addition Phb1 and Phb2 are present in the circulation and can be internalized when added to cultured cells suggesting that the circulating prohibitins may have some regulatory role. This review presents some of the recent developments in prohibitin research and focuses on the similarities in the structure and function of these interesting proteins.

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“…Curiously, visceral fat augmentation was more pronounced in female Mito-Ob and brown fat was more increased in male Mito-Ob mouse [62]. This obese phenotype could be explained by the fact that PHB1 may inhibit pyruvate carboxylase (PC) and, as a consequence, diminishes insulin-stimulated oxidation of glucose and fatty acid in mouse adipocytes [63]. PC inhibition would lead to oxaloacetate depletion and tricarboxylic acid cycle impairment, inhibiting cataplerosis and glyceroneogenesis (lipid accumulation).…”

Section: Overview Of Mitochondrial Relevance In White Adipocytesmentioning

confidence: 99%

Mitochondrial Actions for Fat Browning and Energy Expenditure in White Adipose Tissue

Pbm¹,

Lopes²,

Alonso-Vale³

2016

Journal of Obesity and Overweight

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Obesity can be defined as the disruption in the balance between fuel intake and energy expenditure in favor of energy conservation. Together with type 2 diabetes (T2DM), these are the two of the most prevalent diseases affecting modern societies, arising mostly by changes in eating habits and a sedentary lifestyle associated with poorly known genetic determinants. Obesity predisposes to the so-called metabolic syndrome, which includes inflammation, hypertension, T2DM and cardiovascular diseases [1]. Obesity is imposing an increasingly heavy burden on the world's population in rich and poor nations alike, with almost 30 percent of people globally now either obese (BMI ≥ 30) or overweight (BMI ≥ 25) [2]. In fact, the number of overweight and obese people rose from 857 million in 1980 to 2.1 billion in 2013 [2]. Recently, obesity and metabolic syndrome were associated with mitochondrial dysfunction and deranged regulation of metabolic genes [3]. Interestingly, mitochondria of obese individuals seem to be different from those of lean individuals. Mitochondria from obese individuals display lower energy-generating capacity, less defined inner membranes and reduced fatty acid oxidation (FAO) [4]. AbstractWhite adipose tissue (WAT) is an endocrine organ with crucial role in the development of obesity and related diseases. White adipocytes have less mitochondria than brown adipocytes; nevertheless, there is an increasing body of evidence showing that mitochondrial parameters play a relevant role in WAT physiology, such as proliferation, differentiation and triacylglycerol storage levels. These parameters comprise mitochondria turnover, oxidative capacity, uncoupling, reactive oxygen species levels and oxygen consumption. In addition, the existence of beige (brown in white) adipose tissue and the transdifferatiation of WAT in brown adipose tissue are intrinsically related to mitochondria activity. Herein we highlight that the concerted action of stimulated lipolysis, mitochondrial oxidative metabolism and uncoupling (futile cycle) can enhance WAT energy expenditure. We consider WAT mitochondrial function a promising target for the development of therapies tackling lipotoxicity, obesity and related diseases. White adipose tissue (WAT) is the main tissue linked to obesity. WAT represents around 10% of total body weight in lean adults and more than 50% in obese individuals [5]. WAT is composed of mature adipocytes and the stromal-vascular fraction that contains preadipose cells (or adipoblasts), fibroblasts, immune cells, and blood vessel-associated cells [6]. A single and large lipid droplet occupies most of the white adipocyte volume and WAT copes with obesity either expanding (hypertrophy) or recruiting new cells (hyperplasia) [7]. WAT secretes an array of peptide hormones called adipokines (including leptin and adiponectin), which regulate neurological activities such as appetite and behavior, metabolic activities of peripheral tissues [8] and produce several pro-inflammatory cytokines, such as tumor necrosis factor alp...

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Prohibitin attenuates insulin‐stimulated glucose and fatty acid oxidation in adipose tissue by inhibition of pyruvate carboxylase

Cited by 55 publications

References 28 publications

Prohibitin has an important role in adipocyte differentiation

Prohibitin has an important role in adipocyte differentiation

The Prohibitins: emerging roles in diverse functions

Mitochondrial Actions for Fat Browning and Energy Expenditure in White Adipose Tissue

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