Downregulation of Adipose Tissue Fatty Acid Trafficking in Obesity

McQuaid, Siobhán; Hodson, Leanne; Neville, Matthew J.; Dennis, Andrea; Cheeseman, Jane; Humphreys, Sandy M.; Ruge, Toralph; Gilbert, M.; Fielding, Barbara A.; Frayn, Keith N.; Karpe, Fredrik

doi:10.2337/db10-0867

Cited by 331 publications

(330 citation statements)

References 35 publications

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“…This suggests that higher NEFA flux in postmenopausal women is a result of estrogen depletion. R a NEFA, when corrected for fat mass, was significantly lower with increasing abdominal obesity, in agreement with the concept of downregulated adipose tissue FA trafficking in obesity with reduced expression of lipolytic genes such as hormone‐sensitive lipase and adipose triglyceride lipase 44. The relationship between obesity, insulin resistance, and lipolysis is not clear in the literature and has been elegantly reviewed 45.…”

Section: Discussionsupporting

confidence: 71%

Menopausal Status and Abdominal Obesity Are Significant Determinants of Hepatic Lipid Metabolism in Women

Hodson

Banerjee

Rial

et al. 2015

JAHA

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BackgroundAndroid fat distribution (abdominal obesity) is associated with insulin resistance, hepatic steatosis, and greater secretion of large very low‐density lipoprotein (VLDL) particles in men. Since abdominal obesity is becoming increasingly prevalent in women, we aimed to investigate the relationship between android fat and hepatic lipid metabolism in pre‐ and postmenopausal women.Methods and ResultsWe used a combination of stable isotope tracer techniques to investigate intrahepatic fatty acid synthesis and partitioning in 29 lean and 29 abdominally obese women (android fat/total fat 0.065 [0.02 to 0.08] and 0.095 [0.08 to 0.11], respectively). Thirty women were premenopausal aged 35 to 45 and they were matched for abdominal obesity with 28 postmenopausal women aged 55 to 65. As anticipated, abdominal obese women were more insulin resistant with enhanced hepatic secretion of large (404±30 versus 268±26 mg/kg lean mass, P<0.001) but not small VLDL (160±11 versus 142±13). However, postmenopausal status had a pronounced effect on the characteristics of small VLDL particles, which were considerably triglyceride‐enriched (production ratio of VLDL 2‐ triglyceride:apolipoprotein B 30±5.3 versus 19±1.6, P<0.05). In contrast to postmenopausal women, there was a tight control of hepatic fatty acid metabolism and triglyceride production in premenopausal women, whereby oxidation (r s=−0.49, P=0.006), de novo lipogenesis (r s=0.55, P=0.003), and desaturation (r s=0.48, P=0.012) were closely correlated with abdominal obesity‐driven large VLDL‐triglyceride secretion rate.ConclusionsIn women, abdominal obesity is a major driver of hepatic large VLDL particle secretion, whereas postmenopausal status was characterized by increased small VLDL particle size. These data provide a mechanistic basis for the hyperlipidemia observed in postmenopausal obesity.

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Section: Discussionsupporting

confidence: 71%

Menopausal Status and Abdominal Obesity Are Significant Determinants of Hepatic Lipid Metabolism in Women

Hodson

Banerjee

Rial

et al. 2015

JAHA

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“…The relatively higher metabolic activity in abdominal VF fat compared with SC fat depot is well documented (34), but the metabolic potential in deep SC depots has been likened to VF fat (29,35). This metabolic similarity is attributed to the restricted capacity of peripheral fat depot to store excessive energy, leading to overflow of energy into other fat depots such as deep SC and VF compartments (36). Research has shown that adipocytes from the abdominal deep depots are metabolically superior to superficial SC compartments (29), thereby contributing significantly to global GU.…”

Section: Discussionmentioning

confidence: 96%

Effect of Bariatric Surgery on Adipose Tissue Glucose Metabolism in Different Depots in Patients With or Without Type 2 Diabetes

et al. 2015

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OBJECTIVEWe investigated fat distribution and tissue-specific insulin-stimulated glucose uptake (GU) in seven fat compartments (visceral and subcutaneous) and skeletal muscle in morbidly obese patients with (T2D) and without (ND) type 2 diabetes before and 6 months after bariatric surgery. RESEARCH DESIGN AND METHODSA total of 23 obese patients (BMI 43.0 6 3.6 kg/m 2 ; 9 T2D and 14 ND) were recruited from a larger, randomized multicenter SLEEVEPASS study. MRI (for fat distribution) and [18 F]-fluorodeoxyglucose PET (for GU) studies were performed for the obese patients before and 6 months postsurgery; 10 lean subjects served as control subjects and were studied once. RESULTSAt baseline, visceral fat GU was 30 6 7% of muscle GU in control subjects and 57 6 5% in obese patients. Visceral and deep subcutaneous fat were more abundant (despite same total fat mass) and less insulin sensitive in T2D than ND; in both, GU was impaired compared with control subjects. Postsurgery, visceral fat mass decreased (∼40%) more than subcutaneous fat (7%). Tissue-specific GU was improved, but not normalized, at all sites in T2D and ND alike. The contribution of visceral fat to whole-body GU was greater in T2D than ND but decreased similarly with surgery. Subcutaneous fat made a fourfold greater contribution to whole-body GU in obese versus lean subjects (15% vs. 4%) both before and after surgery. CONCLUSIONSBariatric surgery leads to sustained weight loss and improves tissue-specific glucose metabolism in morbidly obese patients. We conclude that 1) enhanced visceral fat accumulation is a feature of T2D, 2) severe obesity compromises muscle insulin sensitivity more than fat insulin sensitivity, and 3) fat mass expansion is a sink for plasma glucose.Visceral fat (VF) and subcutaneous fat (SC) are structurally, metabolically, and functionally distinct, albeit both contribute to obesity (1). Abdominal SC fat has clearly defined, metabolically distinct deep and superficial layers separated by the Scarpa fascia (2,3). Research suggests that the deep layers are metabolically more active

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“…Perturbed lipid storage (20), enhanced inflammation (21,22), and altered adipokine signaling (23) have all been proposed as mechanisms for obesity-related metabolic complications. The cellular or mechanistic basis for these pathways may involve a reduced capacity to recruit and renew adipocytes, thus limiting AT expandability (24), induction of innate immune mechanisms, or the activation of cellular stress pathways (25).…”

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confidence: 99%

Distinct Developmental Profile of Lower-Body Adipose Tissue Defines Resistance Against Obesity-Associated Metabolic Complications

et al. 2014

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Upper-and lower-body fat depots exhibit opposing associations with obesity-related metabolic disease. We defined the relationship between DEXA-quantified fat depots and diabetes/cardiovascular risk factors in a healthy population-based cohort (n = 3,399). Gynoid fat mass correlated negatively with insulin resistance after total fat mass adjustment, whereas the opposite was seen for abdominal fat. Paired transcriptomic analysis of gluteal subcutaneous adipose tissue (GSAT) and abdominal subcutaneous adipose tissue (ASAT) was performed across the BMI spectrum (n = 49; 21.4-45.5 kg/m 2 ). In both depots, energy-generating metabolic genes were negatively associated and inflammatory genes were positively associated with obesity. However, associations were significantly weaker in GSAT. At the systemic level, arteriovenous release of the proinflammatory cytokine interleukin-6 (n = 34) was lower from GSAT than ASAT. Isolated preadipocytes retained a depotspecific transcriptional "memory" of embryonic developmental genes and exhibited differential promoter DNA methylation of selected genes (HOTAIR, TBX5) between GSAT and ASAT. Short hairpin RNA-mediated silencing identified TBX5 as a regulator of preadipocyte proliferation and adipogenic differentiation in ASAT. In conclusion, intrinsic differences in the expression of developmental genes in regional adipocytes provide a mechanistic basis for diversity in adipose tissue (AT) function. The less inflammatory nature of lower-body AT offers insight into the opposing metabolic disease risk associations between upper-and lower-body obesity.Lower-body fat accumulation, as opposed to central obesity, is inversely associated with metabolic risk factors, including hyperinsulinemia, dyslipidemia, and hypertension (1), and is also associated with a reduced incidence of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) (2,3). Conversely, loss of lower-body fat during weight reduction relates to adverse changes in blood lipid and glucose profiles as well as blood pressure (4).

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Downregulation of Adipose Tissue Fatty Acid Trafficking in Obesity

Cited by 331 publications

References 35 publications

Menopausal Status and Abdominal Obesity Are Significant Determinants of Hepatic Lipid Metabolism in Women

Menopausal Status and Abdominal Obesity Are Significant Determinants of Hepatic Lipid Metabolism in Women

Effect of Bariatric Surgery on Adipose Tissue Glucose Metabolism in Different Depots in Patients With or Without Type 2 Diabetes

Distinct Developmental Profile of Lower-Body Adipose Tissue Defines Resistance Against Obesity-Associated Metabolic Complications

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