<i>Abcc5</i> Knockout Mice Have Lower Fat Mass and Increased Levels of Circulating GLP‐1

Cyranka, Małgorzata; Veprik, Anna; McKay, Eleanor J; Loon, Nienke van; Thijsse, Amber; Cotter, Luke; Hare, Nisha; Saibudeen, Affan; Lingam, Swathi; Pires, Elisabete; Larraufie, Pierre; Reimann, Frank; Gribble, Fiona M.; Stewart, Michelle; Bentley, Elizabeth; Lear, Pamela; McCullagh, James; Cantley, James; Cox, Roger; Wet, Heidi de

doi:10.1002/oby.22521

Cited by 11 publications

(10 citation statements)

References 38 publications

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“…Recent studies in mice showed that lack of Mrp5 decreased body and adipose tissue weights. 41 These phenotypic changes in Mrp5 −/− mice further support that increased adipogenesis observed in our study is specific toward lack of Mrp4 activity. In Mrp4 −/− mice, along with an increase in adipose tissue mass and adipocyte hypertrophy, plasma leptin levels were also increased.…”

Section: Discussionsupporting

confidence: 88%

Multidrug resistance‐associated protein 4 (Mrp4) is a novel genetic factor in the pathogenesis of obesity and diabetes

Donepudi

Lee

et al. 2021

FASEB j.

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Obesity and diabetes have reached epidemic proportions globally. In the United States alone, almost 35% of the adult population are overweight and 12.2% are diabetic. 1,2 Both obesity and diabetes are considered major risk factors for cardiovascular disease (CVD). 3,4 Specifically, abdominal obesity is known to increase the risk of CVD through increased insulin resistance and inflammatory abnormalities. 3,5 An increase in adiposity (increase in adipose tissue

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Section: Discussionsupporting

confidence: 88%

Multidrug resistance‐associated protein 4 (Mrp4) is a novel genetic factor in the pathogenesis of obesity and diabetes

Donepudi

Lee

et al. 2021

FASEB j.

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“…Independent evidence was used to demonstrate that the mapped cis- genes were differentially expressed in individuals with T2D and IR. This is in line with recent in vivo evidence that a novel T2D cis- gene previously mapped using the same method ( 76 ), ABCC5 , was functionally implicated in diabetes by improving insulin sensitivity and reducing fat mass when knocked-out in mice ( 76 , 77 ). Association mapping using genetic LDU maps, as described by Maniatis et al.…”

Section: Discussionsupporting

confidence: 88%

New Insights Into Mitochondrial Dysfunction at Disease Susceptibility Loci in the Development of Type 2 Diabetes

et al. 2021

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This study investigated the potential genetic mechanisms which underlie adipose tissue mitochondrial dysfunction in Type 2 diabetes (T2D), by systematically identifying nuclear-encoded mitochondrial genes (NEMGs) among the genes regulated by T2D-associated genetic loci. The target genes of these ‘disease loci’ were identified by mapping genetic loci associated with both disease and gene expression levels (expression quantitative trait loci, eQTL) using high resolution genetic maps, with independent estimates co-locating to within a small genetic distance. These co-locating signals were defined as T2D-eQTL and the target genes as T2D cis-genes. In total, 763 cis-genes were associated with T2D-eQTL, of which 50 were NEMGs. Independent gene expression datasets for T2D and insulin resistant cases and controls confirmed that the cis-genes and cis-NEMGs were enriched for differential expression in cases, providing independent validation that genetic maps can identify informative functional genes. Two additional results were consistent with a potential role of T2D-eQTL in regulating the 50 identified cis-NEMGs in the context of T2D risk: (1) the 50 cis-NEMGs showed greater differential expression compared to other NEMGs and (2) other NEMGs showed a trend towards significantly decreased expression if their expression levels correlated more highly with the subset of 50 cis-NEMGs. These 50 cis-NEMGs, which are differentially expressed and associated with mapped T2D disease loci, encode proteins acting within key mitochondrial pathways, including some of current therapeutic interest such as the metabolism of branched-chain amino acids, GABA and biotin.

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“…Cautiously, we also point to ABCC5 , which nearly missed our F ST threshold, but does contain a fixed nonsynonymous SNV in our two populations. The expression of ABCC5 “plays a central role in energy metabolism in mammals,” affecting fat mass and insulin sensitivity in knockout mice and the onset of diabetes in humans ( 58 ). Additionally, the significant overabundance of genes associated with diabetic nephropathy in high F ST windows is consistent with there being different functional pressures on kidney and metabolic function in these two populations.…”

Section: Discussionmentioning

confidence: 99%

The genomics of ecological flexibility, large brains, and long lives in capuchin monkeys revealed with fecalFACS

Orkin

Montague

Tejada‐Martinez

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Ecological flexibility, extended lifespans, and large brains have long intrigued evolutionary biologists, and comparative genomics offers an efficient and effective tool for generating new insights into the evolution of such traits. Studies of capuchin monkeys are particularly well situated to shed light on the selective pressures and genetic underpinnings of local adaptation to diverse habitats, longevity, and brain development. Distributed widely across Central and South America, they are inventive and extractive foragers, known for their sensorimotor intelligence. Capuchins have among the largest relative brain size of any monkey and a lifespan that exceeds 50 y, despite their small (3 to 5 kg) body size. We assemble and annotate a de novo reference genome for Cebus imitator. Through high-depth sequencing of DNA derived from blood, various tissues, and feces via fluorescence-activated cell sorting (fecalFACS) to isolate monkey epithelial cells, we compared genomes of capuchin populations from tropical dry forests and lowland rainforests and identified population divergence in genes involved in water balance, kidney function, and metabolism. Through a comparative genomics approach spanning a wide diversity of mammals, we identified genes under positive selection associated with longevity and brain development. Additionally, we provide a technological advancement in the use of noninvasive genomics for studies of free-ranging mammals. Our intra- and interspecific comparative study of capuchin genomics provides insights into processes underlying local adaptation to diverse and physiologically challenging environments, as well as the molecular basis of brain evolution and longevity.

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Abcc5 Knockout Mice Have Lower Fat Mass and Increased Levels of Circulating GLP‐1

Cited by 11 publications

References 38 publications

Multidrug resistance‐associated protein 4 (Mrp4) is a novel genetic factor in the pathogenesis of obesity and diabetes

Multidrug resistance‐associated protein 4 (Mrp4) is a novel genetic factor in the pathogenesis of obesity and diabetes

New Insights Into Mitochondrial Dysfunction at Disease Susceptibility Loci in the Development of Type 2 Diabetes

The genomics of ecological flexibility, large brains, and long lives in capuchin monkeys revealed with fecalFACS

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