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Role of Mitochondrial Dysfunction in Human Obesity
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
David Albuquerque, Sara Carmo-Silva, Daniel Álvarez-Vaca, Célia Aveleira, Clévio Nóbrega
ROS is an important signaling molecule that indicates positive or negative energy states at the level of AgRP/NPY and POMC neurons. Suppression of ROS diminished POMC cell activation and elevated the activity of AgRP/NPY neurons and feeding, whereas ROS activated POMC neurons and reduced feeding. In ob/ob mice, injection of ROS promoted hunger, and increased levels of hypothalamic ROS which seem to activate POMC neurons and reduced feeding (Drougard et al., 2015). Mitochondrial ROS production is negatively regulated by UCP2 (uncoupling protein 2), which highly expressed in the hypothalamus. In diet induced obese mice, UCP2 can affect POMC activation by reducing ROS levels which are necessary for this neuronal population activity (Diano et al., 2011). In opposition, hypothalamic AMPK activation can promote UCP2 activation, leading to the increase in the number of mitochondria and limiting ROS generation, that culminates in the activation of AgRP/NPY neurons (Coppola et al., 2007; Andrews et al., 2008; Jin and Diano, 2018).
Noninsulin-Dependent Animal Models of Diabetes Mellitus
Published in John H. McNeill, Experimental Models of Diabetes, 2018
Christopher H. S. McIntosh, Raymond A. Pederson
Several uncoupling proteins have now been identified. The original protein cloned (UCP1) was identified as a membrane proton transporter found in mitochondria, expressed specifically in brown adipose tissue. Activation of the protein results in dissipation of the proton gradient and heat production. DNA polymorphisms in human UCP1 were found to correlate with age-associated increases in body fat.406 Mutations in the protein could lead to reduced energy expenditure and, thus, weight gain. UCP1 knockout mice were shown to consume less oxygen in response to a β3-adrenergic receptor agonist and were more sensitive to cold.407 However, neither obesity nor hyperphagia was observed. Since animals in which BAT had been completely ablated developed marked obesity with increasing age, hyperglycemia, marked hyperinsulinemia, and glucose intolerance,408 the mild pathology of the UCP1 knockout was probably due to compensation by UCP2,409,410 therefore, double knockouts are needed to determine the effect of overall UCP ablation. It is of interest that UCP2 is also found in pancreatic islet β-cells, where it is likely to play a role in insulin secretion, and overexpression of leptin resulted in tenfold increases in UCP2 gene expression.411 This suggests that altered UCP2 expression, resulting from loss of leptin responsiveness, could contribute to the development of obesity/NIDDM.
Mitochondrial Function in Diabetes: Pathophysiology and Nutritional Therapeutics
Published in Jeffrey I. Mechanick, Elise M. Brett, Nutritional Strategies for the Diabetic & Prediabetic Patient, 2006
Uncoupling proteins (UCP) are members of the ANT family of anion mitochondrial carriers. They are found on the IM and generically serve as a proton shunt to decrease mitochondrial ROS [71]. Uncoupling proteins can also mediate the effects of free radicals on mitochondrial function. UCP1 parcels protons across the IM and diverts energy from OXPHOS. Single-nucleotide polymorphisms in UCP1 have been associated with T2DM [72]. UCP2 is widely expressed and found in pancreatic β-cells. UCP2 is directly activated by the ROS superoxide and indirectly by fatty acids [73,74]. UCP2 activation increases mitochondrial proton leak and decreases mitochondrial membrane potential [74,75]. This leads to decreased ATP levels and GSIS [74,75]. A negative feedback loop is generated when ROS production declines with the decreased mitochondrial membrane potential leading to a steady state [76]. Superoxide-induced activation of UCP2 is therefore important in the pathogenesis of MTDM. In addition to regulating ROS, UCP2 may also be responsible for peroxisome proliferators-activated receptor α (PPAR-α)-independent exportation of free fatty acids from the mitochondria [77–79]. UCP3 is expressed selectively in skeletal muscle and regulates fatty acid metabolism via mitochondrial thioesterase (MTE-1) gene expression and by stimulating glucose transport [80]. Both UCP3 and MTE1 remove fatty acids from the mitochondrial matrix, which liberates coenzyme A (CoA), allowing higher rates of fatty acid oxidation [81]. Dietary fat, via PPAR-α, and insulin stimulate UCP3 gene expression [77].
Uncoupling proteins: are they involved in vitamin D3 protective effect against high-fat diet-induced cardiac apoptosis in rats?
Published in Archives of Physiology and Biochemistry, 2022
Zienab Alrefaie, Hossam Awad, Khadeejah Alsolami, Enas A. Hamed
Uncoupling refers to a state in which nutrient fuels are oxidised but the energy is not linked to ATP synthesis but dissipated as heat. Uncoupling is mediated by (UCPs 1–4) located on the inner mitochondrial membrane, although the presence of other proteins has been argued. Emerging functions of UCP2 and UCP3 are broadly different and findings are conflicting depending on the specific uncoupling protein (UCP) and site of expression; upregulation of UCP2 in pancreatic islets may develop insulin insufficiency in type 2 diabetes mellitus, while increased expression of UCP3 in skeletal muscle prevents development of insulin resistance (Chan and Harper 2006). UCPs are pivotal regulators of cellular energy metabolism and mitochondrial dynamics, they mediate a beneficial defence process to decrease reactive species production so guard against cardiomyocyte apoptosis and the same time ensure ATP production for normal cardiomyocyte function. Measuring cardiac UCPs links the mitochondrial function to oxidative status to apoptosis. The implication of UCPs in cardiac apoptosis was not much investigated. So, further evidence concerning UCPs expression in various models and tissues is extremely needed.
CNR2 rs2229579 and COMT Val158Met variants, but not CNR2 rs2501432, IL-17 rs763780 and UCP2 rs659366, contribute to susceptibility to substance use disorder in the Turkish population
Published in Psychiatry and Clinical Psychopharmacology, 2019
Selin Kurnaz, Ahmet Bulent Yazici, Ayse Feyda Nursal, Pinar Cetinay Aydin, Ayca Ongel Atar, Nazan Aydin, Zeliha Kincir, Sacide Pehlivan
Catechol-O-methyltransferase (COMT) is an enzyme found all over the mammalian central nervous system which breaks down the catecholamine neurotransmitters dopamine, epinephrine, and norepinephrine. A common G-to-A transition in exon 4 of the COMT gene, causing a valine (val)-to-methionine (met) substitution at the amino acid position 108 or 158 (depending on the splice variant), results in a four-fold reduction in enzyme activity in met homozygotes, whereas heterozygotes manifest intermediate activity [3]. The endocannabinoid system plays a role in susceptibility to substance abuse. There are two well-defined cannabinoid receptors (CNRs), CNR1/CB1 and CNR2/CB2, that mediate endocannabinoid signalling [4]. CNR2 has been classically defined as the peripheral cannabinoid receptor because CNR2 is expressed principally in some peripheral and immune cells [5]. Uncoupling protein 2 (UCP2) is a member of an anion-carrier protein family found in the mitochondrial inner membrane. In the central nervous system, mammalian UCP2 mRNA and protein expression occurs at highest levels in regions that could be described as high-risk for stress [6]. The Interleukin 17 (IL-17 or IL-17A) is a fundamental pro-inflammatory cytokine that is primarily released from T cells and is now believed to be the defining cytokine of a recently discovered new subset of T-helper cells, Th17 [7]. New studies have reported that cells of the central nervous system also express IL-17.
The influence of ketogenic therapy on the 5 R’s of radiobiology
Published in International Journal of Radiation Biology, 2019
Besides glycolysis, a second important adaption to high mtROS production frequently occurring in cancer cells is uncoupling of OXPHOS and ATP production through over-expression of uncoupling protein 2 (UCP2). This allows protons to leak from the intermembrane space back into the matrix, decreases the mitochondrial membrane potential and thus reduces the emission of mtROS (Mailloux & Harper 2011). UCP2 overexpression is considered a mechanism of RT and chemotherapy resistance and also has a metabolic action by supporting glucose and glutamine fermentation at the expense of mitochondrial oxidation (Vozza et al. 2014). However, this implicates inefficient mitochondrial ATP generation. Fine and colleagues have shown that UCP2 overexpression can be exploited therapeutically through administration of AcAc which led to ATP depletion and growth inhibition (Fine et al. 2009). They generally proposed that an ‘inefficient’ Randle cycle takes place in cancer cells in which glycolysis gets inhibited through free fatty acids and ketone bodies, but the cells would be unable to compensate for the reduced glycolytic ATP production due to uncoupling or general mitochondrial dysfunction.