Pioglitazone increases non-esterified fatty acid clearance in upper body obesity

Shadid, Samyah; Jensen, Michael D.

doi:10.1007/s00125-005-0051-0

Cited by 33 publications

(25 citation statements)

References 47 publications

(75 reference statements)

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“…Our goal was to detect smaller, yet clinically relevant, effects of v-3 fatty acids on adipose tissue insulin resistance, such as those observed with a 10% weight loss due to a comprehensive lifestyle intervention. In a previous study that used this approach to help obese adults with insulin resistance, we found that insulin-suppressed fatty acid flux improved by 38% 6 46% and insulin-stimulated glucose disposal increased by 30% (35). Although not "normal," we estimated that this degree of improvement would be clinically meaningful, in line with the observations of Magkos et al (36).…”

Section: Power and Statistical Analysissupporting

confidence: 76%

Very-long-chain ω-3 fatty acid supplements and adipose tissue functions: a randomized controlled trial

Hames¹,

Morgan‐Bathke²,

Harteneck³

et al. 2017

The American Journal of Clinical Nutrition

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Section: Power and Statistical Analysissupporting

confidence: 76%

Very-long-chain ω-3 fatty acid supplements and adipose tissue functions: a randomized controlled trial

Hames¹,

Morgan‐Bathke²,

Harteneck³

et al. 2017

The American Journal of Clinical Nutrition

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“…Upper-body subcutaneous fat is the source of excess systemic FFAs in both the fasted and fed conditions. Approaches to improving FFA metabolism in obesity include weight loss (71), inhibition of lipolysis (72), and thiazolidinediones (71).…”

Section: Discussionmentioning

confidence: 99%

Thematic review series: Patient-Oriented Research. Free fatty acid metabolism in human obesity

Koutsari

Jensen

2006

Journal of Lipid Research

177

106

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Adipose tissue lipolysis provides circulating FFAs to meet the body's lipid fuel demands. FFA release is well regulated in normal-weight individuals; however, in upperbody obesity, excess lipolysis is commonly seen. This abnormality is considered a cause for at least some of the metabolic defects (dyslipidemia, insulin resistance) associated with upper-body obesity. ''Normal'' lipolysis is sex-specific and largely determined by the individual's resting metabolic rate. Women have greater FFA release rates than men without higher FFA concentrations or greater fatty acid oxidation, indicating that they have greater nonoxidative FFA disposal, although the processes and tissues involved in this phenomenon are unknown. Therefore, women have the advantage of having greater FFA availability without exposing their tissues to higher and potentially harmful FFA concentrations. Upperbody fat is more lipolytically active than lower-body fat in both women and men. FFA released by the visceral fat depot contributes only a small percentage of systemic FFA delivery. Upper-body subcutaneous fat is the dominant contributor to circulating FFAs and the source of the excess FFA release in upper-body obesity. We believe that abnormalities in subcutaneous lipolysis could be more important than those in visceral lipolysis as a cause of peripheral insulin resistance. Understanding the regulation of FFA availability will help to discover new approaches to treat FFA-induced abnormalities in obesity. Obesity is a global public health concern (1-3). It is well established that obesity, particularly upper-body obesity, is a major contributor to chronic disease and disability, such as dyslipidemia, hypertension, type 2 diabetes, and cardiovascular disease (4). A major link between upper-body obesity and metabolic complications is excessive adipose tissue lipolysis. Under normal conditions, FFA release from adipose tissue is well regulated, allowing appropriate availability of FFAs to meet the energy requirements of the tissues. Increased adiposity can result in excess FFA release relative to tissue needs. The resultant higher FFA concentrations can induce muscle (5) and hepatic (6) insulin resistance, endothelial (7) and pancreatic b-cell (8) dysfunction, and increased VLDL triglyceride production (9). Thus, although adipose tissue is an excellent site for storage of energy and can provide FFAs at times of lipid fuel demands, appropriate regulation of its function is necessary for optimal health in humans.Although upper-body obesity has been associated with a number of metabolic abnormalities, lower-body adiposity has been associated with a more favorable metabolic profile (10-13). It is currently unknown whether the accumulation of subcutaneous fat in the lower-body region exerts a direct protective effect against the unfavorable consequences of obesity or merely serves as a marker for the "healthy" regulation of other fat stores. However, these observations illustrate the complexity of the links between obesity, body fat distributio...

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“…plasma NEFA appearance when using these methodologies. However, insulin did not change the specific activity of plasma triglycerides during intravenous infusion of radioactive oleate tracer in humans (37). These potential limitations of our experimental design are therefore unlikely to have affected our conclusions.…”

Section: ͻ0001mentioning

confidence: 55%

“…This raises the possibility that high plasma NEFA levels observed in subjects with insulin resistance may display abnormal regulation of plasma NEFA clearance in addition to increased plasma NEFA appearance. Interestingly, the insulin-sensitizer pioglitazone lowers plasma NEFA concentration by increasing plasma NEFA clearance rate independently of change in plasma NEFA appearance in nondiabetic individuals with abdominal obesity (37).…”

Section: ͻ0001mentioning

confidence: 99%

Mechanism of insulin-stimulated clearance of plasma nonesterified fatty acids in humans

Carpentier¹,

Frisch²,

Brassard³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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Insulin increases plasma nonesterified fatty acid (NEFA) clearance in humans, but whether this is independent of change in plasma NEFA appearance is currently unknown. Nine nondiabetic men (age: 28 Ϯ 3 yr, body mass index: 27.2 Ϯ 1.7 kg/m 2 ) underwent euglycemic clamps to maintain low (LINS) vs. high (HINS) physiological insulin levels for 6 h. An intravenous infusion of heparin ϩ Intralipid (HI) was performed during 4 of the 6 h of the clamps (in the last 4 h at LINS and in the first 4 h at HINS), whereas saline infusion (SAL) was administered in the remaining 2 h to modulate plasma NEFA levels independently of plasma insulin levels. Four experimental conditions were obtained in each individual: LINS with saline (LINS/SAL) and with HI infusion (LINS/HI) and HINS with saline (HINS/SAL) and with HI infusion (HINS/HI). Plasma palmitate appearance during HINS/SAL was lower than during the three other experimental conditions (P Ͻ 0.05). In contrast, plasma linoleate appearance, as expected, was increased by HI independently of insulin level (P Ͻ 0.02). Plasma palmitate clearance during HINS/SAL was higher than LINS/SAL and LINS/HI (P Ͻ 0.008), and this increase was blunted during HINS/HI. We observed a linear decrease in plasma palmitate clearance with increasing plasma NEFA appearance independent of insulin levels. Plasma NEFA levels increased exponentially with increase in plasma NEFA appearance. We conclude that insulin stimulates plasma NEFA clearance by reducing the endogenous appearance rate of NEFA. The relationship between plasma NEFA level and appearance rate is nonlinear.human; insulin action; lipid metabolism; fatty acid metabolism UNDERSTANDING THE REGULATION of plasma nonesterified fatty acid (NEFA) is very important to elucidate its potential role in the development of various pathological conditions, including type 2 diabetes (27). Prolonged experimental elevation of plasma NEFA in humans reproduces the cardinal pathophysiological features of type 2 diabetes, including reduced insulinmediated glucose utilization, impaired glucose-mediated insulin secretion, and increased endogenous glucose production (10, 36, 39). Epidemiological studies have linked elevated plasma NEFA levels to insulin resistance and type 2 diabetes (15,26,35), and reduced suppression of postprandial plasma NEFA concentration is among the earliest metabolic abnormalities seen in the natural history of type 2 diabetes (3).Insulin potently suppresses plasma NEFA appearance. It is often assumed that plasma NEFA level is an accurate reflection of plasma NEFA appearance rate in various physiological and pathophysiological conditions known to affect plasma NEFA levels through change in plasma insulin level, i.e., that plasma NEFA clearance does not change with changing levels of plasma insulin. However, this may not necessarily be the case, because insulin has been shown to stimulate NEFA transport across plasma cell membranes (6). Elevation of plasma insulin level was associated with enhanced plasma NEFA clearance in human studies durin...

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Pioglitazone increases non-esterified fatty acid clearance in upper body obesity

Cited by 33 publications

References 47 publications

Very-long-chain ω-3 fatty acid supplements and adipose tissue functions: a randomized controlled trial

Very-long-chain ω-3 fatty acid supplements and adipose tissue functions: a randomized controlled trial

Thematic review series: Patient-Oriented Research. Free fatty acid metabolism in human obesity

Mechanism of insulin-stimulated clearance of plasma nonesterified fatty acids in humans

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