Obesity and Insulin Resistance Are Inversely Associated with Serum and Adipose Tissue Carotenoid Concentrations in Adults

ABSTRACT Background Low tissue concentrations of carotenoids have been suggested to contribute to insulin resistance in obesity. Objectives The objectives of the study were to 1) evaluate the relations of adipose tissue and serum carotenoids with body fat, abdominal fat distribution, muscle, adipose tissue and liver insulin resistance, and dietary intake; 2) evaluate the relations and distributions of carotenoids detected in adipose tissue and serum; and 3) compare serum carotenoids and retinol concentrations in subjects with and without obesity. Methods Post hoc analysis of serum and adipose tissue carotenoids in individuals [n = 80; 31 men, 49 women; age (mean ± SEM): 51.4 ± 1.1 y] who participated in 2 separate studies conducted at the Clinical Research Facility at the Garvan Institute of Medical Research (Sydney) between 2008 and 2013. Retinol, α-carotene, β-carotene, ζ-carotene, lutein, lycopene, phytoene, and phytofluene were measured using HPLC. Body composition was measured by dual-energy X-ray absorptiometry. Insulin resistance was measured by 2-step hyperinsulinemic-euglycemic clamps with deuterated glucose (n = 64), and subcutaneous and visceral abdominal volume and liver and pancreatic fat by MRI (n = 60). Periumbilical subcutaneous fat biopsy was performed and carotenoids and retinol measured in the tissue (n = 16). Results We found that ζ-carotene, phytoene, and phytofluene were stored in considerable amounts in adipose tissue (25% of adipose tissue carotenoids). Carotenoid concentrations in adipose tissue and serum correlated significantly, but they followed different distributions: ζ-carotene was 3-fold higher in adipose tissue compared with serum, while lutein and lycopene made up 20% and 21% of serum carotenoids compared with 2% and 12% of adipose tissue carotenoids, respectively. Liver (P ≤ 0.028) and adipose tissue (P = 0.023), but not muscle (P ≥ 0.16), insulin resistance correlated inversely with many of the serum carotenoids. Conclusions Multiple serum and adipose tissue carotenoids are associated with favorable metabolic traits, including insulin sensitivity in liver and adipose tissue in humans.

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Testosterone therapy decreases subcutaneous fat and adiponectin in aging men

Acta Endocrinologica ◽

10.1530/eje-11-0565 ◽

2012 ◽

Vol 166 (3) ◽

pp. 469-476 ◽

Cited By ~ 42

Author(s):

L Frederiksen ◽

K Højlund ◽

D M Hougaard ◽

T H Mosbech ◽

R Larsen ◽

...

Keyword(s):

Adipose Tissue ◽

Fat Mass ◽

Subcutaneous Fat ◽

Fat Distribution ◽

Controlled Study ◽

Testosterone Therapy ◽

Testosterone Levels ◽

Bioavailable Testosterone ◽

Aging Men ◽

Total Fat

ObjectiveTestosterone therapy increases lean body mass and decreases total fat mass in aging men with low normal testosterone levels. The major challenge is, however, to determine whether the metabolic consequences of testosterone therapy are overall positive. We have previously reported that 6-month testosterone therapy did not improve insulin sensitivity. We investigated the effect of testosterone therapy on regional body fat distribution and on the levels of the insulin-sensitizing adipokine, adiponectin, in aging men with low normal bioavailable testosterone levels.DesignA randomized, double-blinded, placebo-controlled study on 6-month testosterone treatment (gel) in 38 men, aged 60–78 years, with bioavailable testosterone <7.3 nmol/l, and a waist circumference >94 cm.MethodsCentral fat mass (CFM) and lower extremity fat mass (LEFM) were measured by dual X-ray absorptiometry. Subcutaneous abdominal adipose tissue (SAT), visceral adipose tissue (VAT), and thigh subcutaneous fat area (TFA) were measured by magnetic resonance imaging. Adiponectin levels were measured using an in-house immunofluorometric assay. Coefficients (b) represent the placebo-controlled mean effect of intervention.ResultsLEFM was decreased (b=−0.47 kg, P=0.07) while CFM did not change significantly (b=−0.66 kg, P=0.10) during testosterone therapy. SAT (b=−3.0%, P=0.018) and TFA (b=−3.0%, P<0.001) decreased, while VAT (b=1.0%, P=0.54) remained unchanged. Adiponectin levels decreased during testosterone therapy (b=−1.3 mg/l, P=0.001).ConclusionTestosterone therapy decreased subcutaneous fat on the abdomen and lower extremities, but visceral fat was unchanged. Moreover, adiponectin levels were significantly decreased during testosterone therapy.

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Circulating steroid levels as correlates of adipose tissue phenotype in premenopausal women

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2017-0082 ◽

2018 ◽

Vol 0 (0) ◽

Author(s):

Geneviève B. Marchand ◽

Anne-Marie Carreau ◽

Sofia Laforest ◽

Julie-Anne Côté ◽

Marleen Daris ◽

...

Keyword(s):

Adipose Tissue ◽

Plasma Levels ◽

Subcutaneous Fat ◽

Premenopausal Women ◽

Fat Distribution ◽

Adipocyte Size ◽

Fat Percentage ◽

Potential Marker ◽

Liquid Chromatography Tandem Mass ◽

Adipocyte Hypertrophy

AbstractBackgroundObesity-related alterations in the circulating steroid hormone profile remain equivocal in women. Our objective was to identify circulating steroid levels that relate to increased adiposity and altered adipose phenotype in premenopausal women.Materials and methodsIn a sample of 42 premenopausal women [age 46 ± 3 years; body mass index (BMI) 27.1 ± 4.2 kg/m2], 19 plasma steroids were quantified by electrospray ionization-liquid chromatography-tandem mass spectroscopy (ESI-LC-MS/MS). Body composition and fat distribution were assessed by dual-energy X-ray absorptiometry (DXA) and computed tomography (CT), respectively. Markers of adipose tissue function including adipocyte size distributions, radiological attenuation and macrophage infiltration were also analyzed in surgically obtained visceral and subcutaneous fat samples.ResultsMany negative correlations were observed between adiposity measurements such as BMI, body fat percentage or total abdominal adipose tissue area and plasma levels of androstenedione (Δ4) (r = −0.33 to −0.39, p ≤ 0.04), androsterone (ADT) (r = −0.30 to −0.38, p ≤ 0.05) and steroid precursor pregnenolone (PREG) (r = −0.36 to −0.46, p ≤ 0.02). Visceral adipocyte hypertrophy was observed in patients with low PREG concentrations (p < 0.05). Visceral adipose tissue radiologic attenuation, a potential marker of adipocyte size, was also positively correlated with PREG levels (r = 0.33, p < 0.05). Low levels of PREG were related to increased number of macrophages infiltrating visceral and subcutaneous adipose tissue (p < 0.05).ConclusionPlasma levels of androgens and their precursors are lower in women with increased adiposity and visceral adipocyte hypertrophy. Low circulating PREG concentration may represent a marker of adipose tissue dysfunction.

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Hepatic fat is a stronger correlate of key clinical and molecular abnormalities than visceral and abdominal subcutaneous fat in youth

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2019-001126 ◽

2020 ◽

Vol 8 (1) ◽

pp. e001126

Author(s):

Catherine E Cioffi ◽

K M Venkat Narayan ◽

Ken Liu ◽

Karan Uppal ◽

Dean P Jones ◽

...

Keyword(s):

Insulin Resistance ◽

Network Analysis ◽

Subcutaneous Fat ◽

Enrichment Analysis ◽

Fat Distribution ◽

Pathway Enrichment Analysis ◽

Clinical Variables ◽

Pathway Enrichment ◽

Hepatic Fat ◽

Integrative Network

IntroductionBody fat distribution is strongly associated with cardiometabolic disease (CMD), but the relative importance of hepatic fat as an underlying driver remains unclear. Here, we applied a systems biology approach to compare the clinical and molecular subnetworks that correlate with hepatic fat, visceral fat, and abdominal subcutaneous fat distribution.Research design and methodsThis was a cross-sectional sub-study of 283 children/adolescents (7–19 years) from the Yale Pediatric NAFLD Cohort. Untargeted, high-resolution metabolomics (HRM) was performed on plasma and combined with existing clinical variables including hepatic and abdominal fat measured by MRI. Integrative network analysis was coupled with pathway enrichment analysis and multivariable linear regression (MLR) to examine which metabolites and clinical variables associated with each fat depot.ResultsThe data divided into four communities of correlated variables (|r|>0.15, p<0.05) after integrative network analysis. In the largest community, hepatic fat was associated with eight clinical biomarkers, including measures of insulin resistance and dyslipidemia, and 878 metabolite features that were enriched predominantly in amino acid (AA) and lipid pathways in pathway enrichment analysis (p<0.05). Key metabolites associated with hepatic fat included branched-chain AAs (valine and isoleucine/leucine), aromatic AAs (tyrosine and tryptophan), serine, glycine, alanine, and pyruvate, as well as several acylcarnitines and glycerophospholipids (all q<0.05 in MLR adjusted for covariates). The other communities detected in integrative network analysis consisted of abdominal visceral, superficial subcutaneous, and deep subcutaneous fats, but no clinical variables, fewer metabolite features (280, 312, and 74, respectively), and limited findings in pathway analysis.ConclusionsThese data-driven findings show a stronger association of hepatic fat with key CMD risk factors compared with abdominal fats. The molecular network identified using HRM that associated with hepatic fat provides insight into potential mechanisms underlying the hepatic fat–insulin resistance interface in youth.

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Relationships between Composition of Major Fatty Acids and Fat Distribution and Insulin Resistance in Japanese

Journal of Diabetes Research ◽

10.1155/2017/1567467 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Chikako Fujii ◽

Toshihide Kawai ◽

Koichiro Azuma ◽

Yuko Oguma ◽

Fuminori Katsukawa ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acids ◽

Linoleic Acid ◽

Glucose Tolerance ◽

Visceral Fat ◽

Subcutaneous Fat ◽

Fat Distribution ◽

Normal Subjects ◽

Metabolic Parameters ◽

Visceral Fat Area

Objective. The aim of this study was to evaluate the relationships between the composition of free fatty acids (FFAs) and metabolic parameters, including body fat distribution, in Japanese.Methods. The study subjects were 111 Japanese patients (54 males, 57 females). Metabolic parameters and visceral and subcutaneous fat areas as determined by CT scanning at the umbilical level were measured. Glucose tolerance test (GTT) was performed by administering 75 g glucose orally.Results. The percentage of linoleic acid (C18:2), the greatest constituent among FFAs, was negatively correlated with visceral fat area (r=−0.411,p<0.0001), fasting glucose (r=−0.330,p<0.0001), HbA1c (r=−0.231,p=0.0146), and systolic blood pressure (r=−0.224,p=0.0184). Linoleic acid percentage was also significantly negatively correlated with HOMA-IR (r=−0.416,p<0.0001) by simple correlation. Based on the findings of OGTT, the 111 subjects were classified into three groups: 33 with normal glucose tolerance, 71 with impaired glucose tolerance (IGT), and 7 diabetic subjects. The percentage of serum linoleic acid in diabetic subjects was significantly lower than that in normal subjects.Conclusion. We conclude that serum linoleic acid level is negatively correlated with the accumulation of visceral fat in relation to a reduction of insulin resistance in Japanese subjects.

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The Role of Adipose Tissue in Insulin Resistance in Women of African Ancestry

Journal of Obesity ◽

10.1155/2013/952916 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 16

Author(s):

Julia H. Goedecke ◽

Naomi S. Levitt ◽

Juliet Evans ◽

Nicole Ellman ◽

David John Hume ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

White Women ◽

African Ancestry ◽

Fat Distribution ◽

Future Research ◽

Industrialized Countries ◽

Tissue Biology ◽

Ectopic Fat Deposition

Women of African ancestry, particularly those living in industrialized countries, experience a disproportionately higher prevalence of type 2 diabetes (T2D) compared to their white counterparts. Similarly, obesity and insulin resistance, which are major risk factors for T2D, are greater in black compared to white women. The exact mechanisms underlying these phenomena are not known. This paper will focus on the role of adipose tissue biology. Firstly, the characteristic body fat distribution of women of African ancestry will be discussed, followed by the depot-specific associations with insulin resistance. Factors involved in adipose tissue biology and their relation to insulin sensitivity will then be explored, including the role of sex hormones, glucocorticoid metabolism, lipolysis and adipogenesis, and their consequent effects on adipose tissue hypoxia, oxidative stress, and inflammation. Finally the role of ectopic fat deposition will be discussed. The paper proposes directions for future research, in particular highlighting the need for longitudinal and/or intervention studies to better understand the mechanisms underlying the high prevalence of insulin resistance and T2D in women of African ancestry.

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Inhibition of Angiopoietin-Like 3 (ANGPTL3) Reduces Adipose Tissue Insulin Resistance in Patients With Familial Partial Lipodystrophy

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.100 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A50-A51

Author(s):

Maria Cristina Foss de Freitas ◽

Baris Akinci ◽

Adam Neidert ◽

Rita Hench ◽

Elif A Oral

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Body Fat ◽

Fat Mass ◽

Subcutaneous Fat ◽

Hormonal Changes ◽

Loss Of Function ◽

Partial Lipodystrophy ◽

Number Of Patients ◽

Familial Partial Lipodystrophy

Abstract Familial partial lipodystrophy (FPLD) is a rare disease characterized by selective loss of peripheral subcutaneous fat, usually affecting the trunk and limbs, but preservation in other areas, such as the face and neck. It is usually associated with dyslipidemia and diabetes mellitus, and currently, there are no approved specific therapies for this disease in the US. Reductions in circulating levels of ANGPTL3 either by homologous loss-of-function mutations in humans or by pharmacological inhibition in rodents are associated with reductions in triglyceride (and other atherogenic lipid) levels and protect from atherosclerosis, making it an attractive target for patients with FPLD and metabolic dyslipidemia. We performed a proof-of-concept study to assess the early efficacy and safety of targeting ANGPTL3 via antisense oligonucleotide ISIS-703802 (vupanorsen) in a small number of patients with FPLD. Four patients with FPLD (3F/1M; age range: 39–48; 1 with LMNA R482Q, 1 with LMNA R584H, and 2 with no causative genetic variant), diabetes (HbA1c>6.5%) and hypertriglyceridemia (>250 mg/dL at screening) were included. Patients received the study drug at a subcutaneous dose of 20 mg weekly for 26 weeks. The primary endpoint was the change in triglycerides at week 27. Other end-points of interest measured at the same time points included insulin secretion, sensitivity, lipid and hormonal changes in response to a 5 hour long mixed meal test and body composition measured by dual energy absorptiometry (DEXA). Treatment resulted in a 59.9±26.3 (mean±SD) % of reduction in triglycerides, 54.7±9.8% of reduction in serum ANGPTL3 levels and 50.8±27.4% of reduction in ApoCIII. Treatment with vupanorsen led to a reduction of 209.3±120.4 in adipose tissue insulin resistance (ADIPO-IR) from a baseline of 470.3±114.3 and the area under the curve (AUC) for circulating free fatty acid levels were decreased by 32.1±21.4 mmol/L/min from a baseline of 215.8±55.2 mmol/L/min. Glucose AUC and triglyceride AUC also decreased after treatment (-14.0±5.2 and -60.1±26.5 mg/dL/min, respectively). Analyzing body fat distribution using DEXA, we observed that the fat mass index (FMI) and trunk mass index (TMI) did not change from baseline, but the ratio of total fat mass/ fat mass from limbs decreased by 10.7±12.2. These data show a tendency for redistribution of central body fat to limbs. There were numerous adverse events observed that were related to common serious complications associated with diabetes and FPLD. Although limited, these results suggest that targeting ANGPTL3 with vupanorsen in patients with FPLD may have a therapeutic role by addressing multiple problems.

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MON-685 Lipodystrophy, a Forgotten Syndrome

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1145 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Janet Marie Colón Castellano ◽

Anardi A Agosto Mujica ◽

Jinetsy I Rivera Ortiz ◽

Nydia Burgos Ortega ◽

Nicolle Canales ◽

...

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Adipose Tissue ◽

Glycemic Control ◽

Insulin Pump ◽

Fat Distribution ◽

Insulin Pump Therapy ◽

Metabolic Disturbances ◽

Pump Therapy ◽

Antidiabetic Therapy

Abstract Background: Lipodystrophy comprises a group of heterogenous congenital and acquired disorders. These disorders may present as a complete or partial loss of adipose tissue. The magnitude of lipoatrophy correlates with the severity of the associated metabolic disturbances, which include severe insulin resistance, progressive liver disease, severe dyslipidemia, among others. The most prevalent form of lipodystrophy is related to antiviral use in patients with HIV. However, lipodystrophy occurring unrelated to medication side effect is often missed due to the heterogeneity and rarity of this disorder. Clinical Case: 31 year old female with medical history of type 2 diabetes mellitus, hypertension, mixed dyslipidemia and polycystic ovarian syndrome who was referred to our clinics due to difficult to control hyperglycemia. Family history was limited. She was diagnosed with diabetes mellitus at 12 years old after presenting with polyuria, polydipsia and polyphagia requiring oral antidiabetic therapy. Following poor response, she was started on insulin therapy. At 23 years old, the patient had an episode of pancreatitis associated with hypertriglyceridemia and eruptive xanthomas. Insulin pump therapy with regular U-100 insulin, total daily dose of 308 units, was initiated but failed to improve glycemic control. The patient was referred to our Endocrinology clinics due to high insulin resistance and a glycosylated hemoglobin (A1C) at 12% (n < 6.5%). Physical examination revealed a body mass index of 23 kg/m2, abnormal fat distribution predominantly over the neck and face, and acanthosis nigricans. Abdominal ultrasound revealed fatty liver infiltration consistent with intrabdominal fat deposition. Due to the constellation of the aforementioned findings, the diagnosis of partial lipodystrophy syndrome was presumed. She was started on antidiabetic therapy with metformin, pioglitazone and insulin pump therapy with U-500 insulin, and high-dose statin therapy plus fenofibrate for dyslipidemia. At follow up, the patient showed improvement in glycemic control and an improved lipid profile. She was referred to a geneticist for evaluation. Conclusion: Lipodystrophy syndromes are a group of heterogenous disorders, which may often be overlooked due to their rarity and lack of familiarity by physicians. The diagnosis of lipodystrophy is based on history, abnormal body fat distribution, and metabolic profile. The metabolic disturbances seen in these patients are mainly due to the lack of adipose tissue, which results in impaired energy storage. Early recognition of these syndromes is important because intensive treatment of hyperlipidemia and diabetes prevents development of severe complications. In this case we highlight this rare condition and the successful use of new therapeutic technology with insulin pumps and U-500 insulin in the glycemic control of a patient with lipodystrophy.

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Evaluation of Ethnic Variations in Visceral, Subcutaneous, Intra-Pancreatic, and Intra-Hepatic Fat Depositions by Magnetic Resonance Imaging among New Zealanders

Biomedicines ◽

10.3390/biomedicines8060174 ◽

2020 ◽

Vol 8 (6) ◽

pp. 174

Author(s):

John Zhiyong Yang ◽

Dech Dokpuang ◽

Reza Nemati ◽

Kevin Haokun He ◽

Andy Baige Zheng ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Adipose Tissue ◽

New Zealand ◽

Magnetic Resonance ◽

Fat Distribution ◽

Resonance Imaging ◽

Anthropometric Indices ◽

Pancreatic Fat ◽

Hepatic Fat ◽

Magnetic Resonance Imaging Mri

Anthropometric indices, such as body mass index (BMI), waist circumference (WC), and waist to height ratio (WHtR), have limitations in accurately predicting the pathophysiology of diabetes mellitus, cardiovascular diseases, and metabolic syndrome due to ethnic differences in fat distribution. Recent studies showed that the visceral adipose tissue (VAT) deposition and fat content of internal organs, most notably intra-hepatic and intra-pancreatic fat, has emerged as a more important parameter. In this study, we aimed to assess the coordination between the traditional anthropometric indices and the various fat depositions within different ethnicities in New Zealand. We recruited 104 participants with different ethnic backgrounds, including New Zealand Europeans, Māori (the indigenous people of New Zealand), Pacific Islanders (PI), and Asians. Their weight, height, and WC were measured, and subcutaneous, visceral, intra-hepatic, and intra-pancreatic fat depositions were obtained by magnetic resonance imaging (MRI). The result showed VAT, but not subcutaneous adipose tissue (SAT) depositions at all levels were significantly varied among the three groups. BMI was associated best with L23SAT in NZ Europeans (30%) and L45VAT in Māori/PI (24.3%). WC and WHtR were correlated well with L45SAT in the total population (18.8% and 12.2%, respectively). Intra-pancreatic fat deposition had a positive Pearson relationship with NZ European BMI and Māori/PI WC, but no regression correlation with anthropometric indices. Conventional anthropometric indices did not correspond to the same fat depositions across different ethnic groups.

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Elevated adipose tissue associated IL-2 expression in obesity correlates with metabolic inflammation and insulin resistance

Scientific Reports ◽

10.1038/s41598-020-73347-y ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Shihab Kochumon ◽

Ashraf Al Madhoun ◽

Fatema Al-Rashed ◽

Reeby Thomas ◽

Sardar Sindhu ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Fasting Blood Glucose ◽

Rna Extraction ◽

Subcutaneous Fat ◽

Low Grade ◽

Metabolic Inflammation ◽

Markers Of Inflammation ◽

Immune Alterations ◽

Cluster Of Differentiation

Abstract Adipose tissue (AT) associated cytokines are involved in the development of chronic low-grade inflammation in obese individuals. IL-2, a pleiotropic cytokine, contributes to immune alterations during inflammation. However, the interaction between AT-IL-2 and other inflammatory biomolecules in obesity remains elusive. We investigated whether AT-IL-2 expression was associated with markers of inflammation and insulin resistance in overweight/obese individuals. Subcutaneous fat tissues were collected from 56 individuals (lean/overweight/obese) for RNA extraction. IL-2 and inflammatory mediators were quantified by qRT-PCR and immunohistochemistry. CRP was measured by ELISA. AT-IL-2 expression was higher in obese compared with lean individuals (P < 0.021) and correlated with BMI. IL-2 correlated with interleukins IL-8 and IL-12A (r = 0.333–0.481; p = 0.0001–0.029); as well as with chemokines and their receptors including CCL5, CCL19, CCR2 and CCR5 (r = 0.538–0.677; p < 0.0001). Moreover, IL-2 correlated with toll-like receptors (TLR2, TLR8, TLR10), interferon regulatory factor 5 (IRF5) and cluster of differentiation CD11c (r = 0.282–0.357; p < 0.039). Notably, IL-2 was associated positively with fasting blood glucose (FBG), HbA1c, TGL and CRP (r ≥ 0.423;P ≤ 0.007). In multiple regression analysis, IL-2 is an independent predictor of IL-8, IL-12A, TLR10, TGL and HbA1c. Overall, our data demonstrate that increased expression of the AT-IL-2, in obesity, may represent a novel biomarker for progression of metabolic inflammation and insulin-resistance.

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Plexin D1 determines body fat distribution by regulating the type V collagen microenvironment in visceral adipose tissue

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1416412112 ◽

2015 ◽

Vol 112 (14) ◽

pp. 4363-4368 ◽

Cited By ~ 37

Author(s):

James E. N. Minchin ◽

Ingrid Dahlman ◽

Christopher J. Harvey ◽

Niklas Mejhert ◽

Manvendra K. Singh ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Body Fat ◽

Fat Distribution ◽

Body Fat Distribution ◽

High Fat ◽

Type V ◽

Visceral Adipose

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.

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