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Gene that Controls Body Fat/Lipodystrophy in Belly
(VAT & Subcutaneous Fat) - New Discovery
 
 
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researchers have discovered that a gene called Plexin D1 appears to control both where fat is stored and how fat cells are shaped, known factors in health and the risk of future disease....."This work identifies a new molecular pathway that determines how fat is stored in the body......Plxnd1 regulates body fat distribution by determining the growth characteristics of VAT.....our data suggest that Plxnd1 promotes VAT hypertrophy and growth and insulin resistance in both zebrafish and humans, and identifies PLXND1 as a new target for treatment of metabolic disease........"We think that Plexin D1 is functioning within blood vessels to pattern the environment in visceral fat tissue," said Minchin, who was lead author of the study. That is, the genes that build blood vessels are also setting up structures to house fat cells. "And this role skews the distribution and shape of fat in one direction or another," he said. "It is probably just one of many of different genes that each contribute to overall body shape and metabolic health."
 
Genome-wide association studies have implicated PLXND1 in the regulation of body fat distribution and type 2 diabetes (10). However, a role for PLXND1 in regional adiposity has not been described, nor has direct evidence of a role in human metabolic disease been established. Our data establish three key points. First, Plxnd1 regulates body fat distribution by determining the growth characteristics of VAT. Second, the effect of Plxnd1 in VAT is mediated by Col5a1 and the establishment of an ECM microenvironment that is conducive to hyperplastic growth. Third, Plxnd1 deficiency protects zebrafish from HFD-induced insulin resistance and glucose intolerance, in accord with association data from humans showing that VAT PLXND1 mRNA levels correlate with insulin resistance and type 2 diabetes. Thus, our data suggest that Plxnd1 promotes VAT hypertrophy and growth and insulin resistance in both zebrafish and humans, and identifies PLXND1 as a new target for treatment of metabolic disease.....The relative abundance of VAT and SAT strongly influence susceptibility to metabolic disease. Previous studies suggest that impaired SAT expansion leads to increased lipid accumulation in VAT and subsequent metabolic complications (36-38). As such, SAT acts as a "lipid buffer" that protects other tissues, including VAT, from excessive lipid exposure. In a similar manner, our HFD data suggest that impaired VAT growth in plxnd1 mutants positively influences lipid deposition in SAT
 
https://today.duke.edu/2015/03/fatfish
 
Scientists have known for some time that people who carry a lot of weight around their bellies are more likely to develop diabetes and heart disease than those who have bigger hips and thighs. But what hasn't been clear is why fat accumulates in different places to produce these classic "apple" and "pear" shapes.
 
Now, researchers have discovered that a gene called Plexin D1 appears to control both where fat is stored and how fat cells are shaped, known factors in health and the risk of future disease. Acting on a pattern that emerged in an earlier study of waist-to-hip ratios in 224,000 people, the study (full study below) , which appears March 23 in the Proceedings of the National Academy of Sciences, found that zebrafish that were missing the Plexin D1 gene had less abdominal or visceral fat, the kind that lends some humans a characteristic apple shape. The researchers also showed that these mutant zebrafish were protected from insulin resistance, a precursor of diabetes, even after eating a high-fat diet. "This work identifies a new molecular pathway that determines how fat is stored in the body, and as a result, affects overall metabolic health," said John F. Rawls, Ph.D., senior author of the study and associate professor of molecular genetics and microbiology at Duke University School of Medicine. "Moving forward, the components of that pathway can become potential targets to address the dangers associated with visceral fat accumulation." Unlike the subcutaneous fat that sits beneath the skin of the hips, thighs, and rear of pear-shaped individuals, visceral fat lies deep within the midsection, wedged between vital organs like the heart, liver, intestine, and lungs. From there, the tissue emits hormones and other chemicals that cause inflammation, triggering metabolic diseases like high blood pressure, heart attack, stroke, and diabetes. Despite the clear health implications of body fat distribution, relatively little is known about the genetic basis of body shape. A large international study that appeared in Nature in February began to fill in this gap by looking for regions of the human genome associated with a common metric known as the waist-to-hip ratio, which uses waist measurements as a proxy for visceral fat and hip measurements as a proxy for subcutaneous fat. The researchers analyzed samples from 224,000 people and found dozens of hot spots linked to their waist-hip ratio, including a few near a gene called Plexin D1 which is known to be involved in building blood vessels. Rawls and his postdoctoral fellow James E. Minchin, Ph.D., were curious about how a gene for growing blood vessels might control the storage and shape of fat cells. When they knocked out the Plexin D1 gene in mice, all of the mutant animals died at birth. So they turned to another model organism, the zebrafish, to conduct the rest of their experiments. Because these small aquarium fish are transparent for much of their lives, the researchers could directly visualize how fat was distributed differently between animals that had been genetically engineered to lack Plexin D1 and those with the gene still intact. By using a chemical dye that fluorescently stained all fat cells, the researchers could see that the mutant zebrafish had less visceral fat than their normal counterparts. They also noticed that the shape or morphology of the fat cells themselves was different. The zebrafish without the Plexin D1 gene had visceral fat tissue that was composed of smaller, but more numerous cells, a characteristic known to decrease the risk of insulin resistance and metabolic disease in humans. In contrast, their normal siblings had visceral fat tissue containing larger, but fewer fat cells of the kind known to be more likely to leak inflammatory substances that contribute to illness.
 
To determine how these findings related to metabolic disease, Minchin put the zebrafish on a high-fat diet. After a few weeks of adding egg yolks to their typical chow, Minchin found that the differences in fat distribution between the mutant and the normal zebrafish became even more pronounced. He then gave the fish a glucose tolerance test to see how their bodies responded to sugar. The mutants did a better job of clearing sugar out of their bloodstream and seemed to be protected from developing insulin resistance, a risk factor for diabetes and heart disease. Bolstering the zebrafish findings, collaborators at the Karolinska Institute in Sweden analyzed human patient samples and showed that levels of Plexin D1 were higher in individuals with type 2 diabetes, suggesting it may play a similar role in humans. "We think that Plexin D1 is functioning within blood vessels to pattern the environment in visceral fat tissue," said Minchin, who was lead author of the study. That is, the genes that build blood vessels are also setting up structures to house fat cells. "And this role skews the distribution and shape of fat in one direction or another," he said. "It is probably just one of many of different genes that each contribute to overall body shape and metabolic health." The researchers are actively searching for other genes as well as environmental factors that are involved in the biology of body fat, again using zebrafish models. "Our results indicate that the genetic architecture of body fat distribution is shared between fish and humans, which represents about 450 million years of evolutionary divergence," Rawls said. "For these pathways to have been conserved for so long suggests that they are serving an important role." The research was supported in part by grants from the National Institutes of Health (DK081426, DK091356, DK093399, HL092263, R01HL118768), UNC UCRF Pilot Research Project Award, a Pew Scholars in Biomedical Sciences Award, and American Heart Association Postdoctoral Fellowships (11POST7360004, 13POST1690097). CITATION: "Plexin D1 determines body fat distribution by regulating the type V collagen microenvironment in visceral adipose tissue," James E.N. Minchin, Ingrid Dahlman, Christopher J. Harvey, Niklas Mejhert, Manvendra K. Singh, Jonathan A. Epstein, Jesus Torres-Vazquez, and John F. Rawls. Proceedings of the National Academy of Sciences, March 23, 2015. DOI: 10.1073/pnas.1416412112
 
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Plexin D1 determines body fat distribution by regulating the type V collagen microenvironment in visceral adipose tissue......
 
PNAS Early Edition......March 23, 2015
 
James E. N. Minchina,b, Ingrid Dahlmanc, Christopher J. Harveyb, Niklas Mejhertc, Manvendra K. Singhd,e, Jonathan A. Epsteind, Peter Arnerc, Jesus Torres-Vazquezf, and John F. Rawlsa,b,1
 
aDepartment of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710; bDepartment of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; cDepartment of Medicine, Karolinska Institutet, Karolinska University Hospital, 14186 Stockholm, Sweden; dCell and Developmental Biology and the Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104; eSignature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Graduate Medical School, National Heart Center, 169857 Singapore; and fDepartment of Cell Biology, Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, NY 10016
 
"our findings identify Plxnd1 as a novel regulator of VAT growth, body fat distribution, and insulin sensitivity in both zebrafish and humans."
 
Significance

 
PLEXIN D1 (PLXND1) has been implicated in body fat distribution and type 2 diabetes by genome-wide association studies, but the mechanism is unknown. We show here that Plxnd1 regulates body fat distribution in zebrafish by controlling the visceral adipose tissue (VAT) growth mechanism. Plxnd1 deficiency in zebrafish resulted in induction of a hyperplastic state and reduced lipid deposition in VAT. Regulation of VAT was dependent on the induction of the type V collagen, col5a1, suggesting that Plxnd1 controls body fat distribution by determining the status of VAT extracellular matrix. Plxnd1-deficient zebrafish were protected from high-fat-induced insulin resistance, and human PLXND1 mRNA was positively associated with type 2 diabetes. These results suggest that the role of Plxnd1 in body fat distribution and insulin signaling is conserved from zebrafish to humans.
 
Abstract
 
Genome-wide association studies have implicated PLEXIN D1 (PLXND1) in body fat distribution and type 2 diabetes. However, a role for PLXND1 in regional adiposity and insulin resistance is unknown. Here we use in vivo imaging and genetic analysis in zebrafish to show that Plxnd1 regulates body fat distribution and insulin sensitivity. Plxnd1 deficiency in zebrafish induced hyperplastic morphology in visceral adipose tissue (VAT) and reduced lipid storage. In contrast, subcutaneous adipose tissue (SAT) growth and morphology were unaffected, resulting in altered body fat distribution and a reduced VAT:SAT ratio in zebrafish. A VAT-specific role for Plxnd1 appeared conserved in humans, as PLXND1 mRNA was positively associated with hypertrophic morphology in VAT, but not SAT. In zebrafish plxnd1 mutants, the effect on VAT morphology and body fat distribution was dependent on induction of the extracellular matrix protein collagen type V alpha 1 (col5a1). Furthermore, after high-fat feeding, zebrafish plxnd1 mutant VAT was resistant to expansion, and excess lipid was disproportionately deposited in SAT, leading to an even greater exacerbation of altered body fat distribution. Plxnd1-deficient zebrafish were protected from high-fat-diet-induced insulin resistance, and human VAT PLXND1 mRNA was positively associated with type 2 diabetes, suggesting a conserved role for PLXND1 in insulin sensitivity. Together, our findings identify Plxnd1 as a novel regulator of VAT growth, body fat distribution, and insulin sensitivity in both zebrafish and humans.
 
The regional distribution and morphology of adipose tissue (AT) are strong predictors of metabolic disease (1-3). Excess lipid deposition in visceral AT (VAT; adipose associated with visceral organs) is associated with increased susceptibility to insulin resistance and type 2 diabetes (4), whereas expansion of subcutaneous AT (SAT; adipose between muscle and skin) is associated with reduced risk for metabolic disease and is even protective against hyperglycemia and dyslipidemia (4-7). In turn, hypertrophic AT morphology (few large adipocytes) is associated with insulin resistance and AT dysfunction, whereas hyper plastic AT morphology (many small adipocytes) is associated with improved metabolic parameters (4, 7-9). Therefore, the identification of factors that regulate regional distribution and AT morphology could lead to new therapies to treat metabolic disease.
 
Discussion
 
Genome-wide association studies have implicated PLXND1 in the regulation of body fat distribution and type 2 diabetes (10). However, a role for PLXND1 in regional adiposity has not been described, nor has direct evidence of a role in human metabolic disease been established. Our data establish three key points. First, Plxnd1 regulates body fat distribution by determining the growth characteristics of VAT. Second, the effect of Plxnd1 in VAT is mediated by Col5a1 and the establishment of an ECM microenvironment that is conducive to hyperplastic growth. Third, Plxnd1 deficiency protects zebrafish from HFD-induced insulin resistance and glucose intolerance, in accord with association data from humans showing that VAT PLXND1 mRNA levels correlate with insulin resistance and type 2 diabetes. Thus, our data suggest that Plxnd1 promotes VAT hypertrophy and growth and insulin resistance in both zebrafish and humans, and identifies PLXND1 as a new target for treatment of metabolic disease.
 
We propose a model whereby Plxnd1 regulates the mechanism of VAT growth by determining the status of the VAT ECM microenvironment (Fig. 5E and SI Appendix, Fig. S16). Our data show that in Plxnd1-deficient VAT, the induction of Col5a1 promotes adipocyte proliferation and differentiation, leading to hyperplastic VAT morphology and reduced lipid accumulation. Moreover, our data show that Col5a1 induction in plxnd1 mutants is localized to vascular endothelial cells, suggesting that blood vessels are the source of altered VAT morphology and body fat distribution. In normally fed animals, SAT is not significantly affected by Plxnd1 deficiency. However, after high-fat feeding of plxnd1 mutants, VAT fails to expand, and excess lipid is stored in SAT. Thus, we propose that impaired VAT expansion in plxnd1 mutants leads to increased, and perhaps compensatory, lipid storage in SAT. A VAT-specific role for Plxnd1 is supported by gene expression data from humans that show PLXND1 mRNA is positively correlated with hypertrophic morphology in VAT, with no association found between morphology and PLXND1 in SAT.
 
The relative abundance of VAT and SAT strongly influence susceptibility to metabolic disease. Previous studies suggest that impaired SAT expansion leads to increased lipid accumulation in VAT and subsequent metabolic complications (36-38). As such, SAT acts as a "lipid buffer" that protects other tissues, including VAT, from excessive lipid exposure. In a similar manner, our HFD data suggest that impaired VAT growth in plxnd1 mutants positively influences lipid deposition in SAT. Intriguingly, the thiazolidinedione class of peroxisome-proliferator activated receptor ligands influences body fat distribution and decreases VAT:SAT ratio (39-41). Interestingly, we observe an increase in pparg mRNA in both control and HFD-fed plxnd1 VAT, suggesting pparg induction within VAT may underlie the observed altered body fat distribution. In accordance, thiazolidinedione treatment has been shown to solely influence VAT growth in humans (40), although other studies suggest SAT is also affected (39). An increased proportion of small adipocytes in SAT is correlated with metabolic disturbance (38, 42). We found plxnd1 mutants had an increased ratio of small:large LDs in VAT (SI Appendix, Fig. S17); however, as we observe increased proliferation and differentiation in plxnd1 mutant VAT, we believe this phenotype is likely different from the impaired differentiation observed in human insulin resistant SAT (38).
 
Type V collagens have not been previously implicated in the regulation of in vivo AT growth or body fat distribution. Type V collagens are expressed by preadipocytes (43) and have a stimulatory effect on adipocyte hyperplasia (19). Indeed, adipocyte differentiation is characterized by increased collagen V accumulation, followed by a decline in collagen V as adipose maturation proceeds (20). Thus, collagen V is associated with "hyperplastic" adipose conditions. Our data support a role for Col5a1 in hyperplastic AT morphology. We speculate that Col5a1 may be selectively induced in situations in which hyper plastic growth is needed, such as insulin-resistant AT. Collagen in obese AT correlates with insulin resistance and metabolic disease and is thus often considered pathological (44). Our data suggest that increased Col5a1 is metabolically beneficial. Intriguingly, AT of healthy children contains increased collagen accumulation that is correlated with decreased adipocyte size and body mass index (45), suggesting AT collagen can be beneficial to AT growth and expansion in certain human contexts.
 
 
 
 
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