Prohibitin Overexpression in Adipocytes Induces Mitochondrial Biogenesis, Leads to Obesity Development, and Affects Glucose Homeostasis in a Sex-Specific Manner

Ande, Sudharsana Rao; Nguyen, Khanh; Padilla-Meier, G. Pauline; Wahida, Wahida; Nyomba, B. L. Grégoire; Mishra, Suresh

doi:10.2337/db13-1807

Cited by 57 publications

(131 citation statements)

References 24 publications

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“…The anti-tumorigenic versus pro-tumorigenic role of PHB is likely dependent upon its sub-cellular localization, type of cancer tissue, as well as any involved signaling pathways [3,13]. Increased expression of PHB modulates signaling between mitochondria and the nucleus for mitochondrial biogenesis [14].…”

Section: Introductionmentioning

confidence: 99%

Effect of estrogen on expression of prohibitin in white adipose tissue and liver of diet-induced obese rats

Choi

Chaudhari

et al. 2015

Mol Cell Biochem

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Prohibitin (PHB) is a ubiquitously expressed and highly conserved protein that participates in diverse cellular processes, and its functions are linked to a variety of diseases. In the present study, to explore transcriptional activation and signaling pathways involved in PHB regulation in response to sex hormone treatment, we investigated the effects of estrogen (17-β-estradiol, E2) on regulation of PHB in several metabolic tissues from male and female rats. Elevated expression of PHB was prominent in white adipose tissue (WAT) and the liver, and E2 stimulated PHB expression in both ND and HFD-fed rats. To further confirm the expression of PHB which was increased in WAT and the liver, we analyzed PHB expression levels in 3T3-L1 and C9 cells after the treatment of E2. Transcription and protein levels of PHB were dose-dependently increased by E2 treatment in both cell types, supporting our in vivo data. To further evaluate the possible role of E2 in elevation of PHB via estrogen receptors (ER), the potent ER inhibitor fulvestrant was treated to 3T3-L1 and C9 cells. Fulvestrant markedly suppressed both transcription and protein levels of PHB, suggesting that PHB expression in both tissues may be regulated through ERs. GeneMANIA, a predictive web interface, was used to show that Phb is regulated via the intracellular steroid hormone receptor signaling pathway, suggesting a role for ERs in expression of Phb as well as other metabolically important genes. Based on these results, we expect that targeting PHB would be a useful therapeutic approach for treatment of obesity.

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Section: Introductionmentioning

confidence: 99%

Effect of estrogen on expression of prohibitin in white adipose tissue and liver of diet-induced obese rats

Choi

Chaudhari

et al. 2015

Mol Cell Biochem

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“…Conversely, Mito-Ob and m-Mito-Ob mice share obesity and metabolic phenotype, but differ in immune phenotype and, as a result, develop two different, obesity-linked, types of tumor in a mutually exclusive manner. 46,50 Moreover, the development of adult onset type 1 diabetes or tumor in the male m-MitoOb mice in a mutually exclusive and context-dependent manner 46,71 further supports the notion that pre-existing immune status plays a crucial role in obesity-related diseases, including diabetes and different types of cancer. Furthermore, it is possible that the development of insulin resistance as a result of immune dysregulation may be one of the mechanisms for the development of type 2 diabetes and its associated cancer in lean subjects.…”

Section: Metabolic and Immune Dysregulation-common To Obesity-linked mentioning

confidence: 60%

“…The obese phenotype of transgenic mice overexpressing PHB in adipocytes (Mito-Ob) confirmed that PHB, indeed, has a role in the regulation of adipose tissue homeostasis, which appears to be primarily mediated though its mitochondrial function. 50 In addition to adipocytes, PHB may contribute to metabolic homeostasis through its role in pancreatic b-cells. This is because PHB has important role in mitochondrial function, which is crucial for b-cell function, and PHB level has been reported to be upregulated in murine and human pancreatic b-cell lines as a protective response to oxidative stress.…”

Section: Phb In Metabolic Homeostasismentioning

confidence: 99%

Prohibitin – At the crossroads of obesity-linked diabetes and cancer

Mishra

Nyomba

2017

Exp Biol Med (Maywood)

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Impact statementProhibitin (PHB) is ubiquitously expressed and plays a role in adipocyte-immune cell cross-talk. Both male and female transgenic mice expressing wild-type PHB in adipose tissue and in macrophages are obese, but only males develop diabetes and liver cancer. When the mice express PHB mutated on tyrosine-114 in adipocytes and macrophages, both males and females are still obese, but none develops liver cancer; instead, males develop lymph node tumors. Adipocyte specific functions of PHB are mediated through its mitochondrial function, whereas its immune functions are mediated in a phosphorylation-dependent manner. Thus, PHB appears to be an important molecule linking obesity, diabetes, and cancer. In addition, this link appears to be affected by sex steroids. Therefore, targeting PHB may lead to a better understanding of the pathogenesis of obesity, diabetes and cancer. AbstractThe promoter of a gene that is selectively expressed in just a few cell types provides unique opportunities to study: (1) the pleiotropic function of a protein in two different cell types including the cell compartment specific function, and (2) the crosstalk between two cell/ tissue types at the systemic level. This is not possible with a ubiquitous or a highly specific gene promoter. The adipocyte protein-2 (aP2) is one such gene. It is primarily expressed in adipocytes, but also selectively in monocytic macrophages and dendritic cells, among various immune cell types. Thus, the adipocyte protein-2 gene promoter provides an opportunity to simultaneously manipulate adipose and immune functions in a transgenic animal. Prohibitin (PHB) is a pleiotropic protein that has roles in both adipocytes and immune cells. Adipocyte specific functions of prohibitin are mediated through its mitochondrial function, whereas its immune functions are mediated in a phosphorylation-dependent manner. We capitalized on this attribute of prohibitin to explore the crosstalk between adipose and immune functions, and to discern mitochondrial and plasma membrane-associated cell signaling functions of prohibitin, by expressing wild type prohibitin (Mito-Ob) and a phospho-mutant form of prohibitin (m-Mito-Ob) from the protein-2 gene promoter, individually. Both transgenic mice develop obesity in a sex-neutral manner, but develop obesity-related metabolic dysregulation in a male sex-specific manner. Subsequently, the male Mito-Ob mice spontaneously developed type 2 diabetes and liver cancer, whereas the male m-Mito-Ob mice developed lymph node tumors or autoimmune diabetes in a context-dependent manner. This review provides a point of view on the role of prohibitin in mediating sex differences in adipose and immune functions at the systemic level. We discuss the unique attributes of prohibitin and provide a new paradigm in adipose-immune crosstalk mediated through a pleiotropic protein.

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Section: Overview Of Mitochondrial Relevance In White Adipocytesmentioning

confidence: 99%

“…On the contrary, in a mouse model overexpressing PHB in adipocytes via aP2 promoter (Mito-Ob mouse), it was observed that PHB overexpression led to mitochondrial biogenesis upregulation but also to obesity [62]. 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].…”

Section: Journal Of Obesity and Overweightmentioning

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 Overexpression in Adipocytes Induces Mitochondrial Biogenesis, Leads to Obesity Development, and Affects Glucose Homeostasis in a Sex-Specific Manner

Cited by 57 publications

References 24 publications

Effect of estrogen on expression of prohibitin in white adipose tissue and liver of diet-induced obese rats

Effect of estrogen on expression of prohibitin in white adipose tissue and liver of diet-induced obese rats

Prohibitin – At the crossroads of obesity-linked diabetes and cancer

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

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