Fatty Acids, Obesity, and Insulin Resistance: Time for a Reevaluation

Karpe, Fredrik; Dickmann, Julian R.; Frayn, Keith N.

doi:10.2337/db11-0425

Cited by 715 publications

(663 citation statements)

References 83 publications

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“…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. At a whole body level, lipolysis was similar in lean and abdominally obese groups, but the contribution of systemic FA to increased VLDL 1 ‐TG was significantly higher in abdominally obese women, as was the contribution of nonsystemic FA, with a tendency toward increased de novo hepatic FA secretion indicating an upregulation of secretion of FA from all sources.…”

Section: Discussionsupporting

confidence: 74%

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: 74%

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

Hodson

Banerjee

Rial

et al. 2015

JAHA

Self Cite

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“…Lipid elevation can give rise to diacylglycerols, which contribute to insulin resistance [1]. However, NEFA concentrations vary substantially in obese and T2D patients and may be higher during short-term fasting even in insulin-sensitive humans [7]. Nevertheless, NEFA elevation during lipid infusion or prolonged fasting leads to insulin resistance with a subsequent reduction in muscle oxidative capacity [8].…”

Section: Discussionmentioning

confidence: 99%

Metabolic flexibility and oxidative capacity independently associate with insulin sensitivity in individuals with newly diagnosed type 2 diabetes

et al. 2016

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Aims/hypothesis Both inherited and acquired insulin resistance have been associated with abnormal muscle mitochondrial function. At whole-body level, maximal oxygen uptake (V : O 2max ) and/or metabolic flexibility (as given by ΔRQ) reflect certain features of mitochondrial function. This study tests the hypotheses (1) that V : O 2max and ΔRQ correlate tightly with each other and with insulin sensitivity and (2) that glycaemia, lipidaemia or subclinical inflammation would explain such relationships. Methods Near-normoglycaemic individuals with type 2 diabetes mellitus (n = 136) with a short known disease duration (<12 months) underwent cycling spiroergometry, indirect calorimetry and hyperinsulinaemic-euglycaemic clamp tests. Results Both V : O 2max (r = 0.39, p < 0.0001) and ΔRQ (r = 0.32, p < 0.0001) correlated positively with whole-body insulin sensitivity, even after adjusting for anthropometric variables, glycaemia and glucose-lowering medication, but not after adjusting for NEFA. V : O 2max further correlated negatively with circulating high-sensitivity C-reactive protein concentration. However, V : O 2max did not relate to ΔRQ, even after adjusting for whole-body insulin sensitivity.

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“…41. There is widespread acceptance that non‐esterified fatty acids (NEFA) can mediate insulin resistance, and study results suggest that the reported insulin‐mediated reduction in CNS activity in obese people may be associated with elevated levels of NEFA 51. Studies have shown that insulin‐mediated cerebrocortical activity is reduced in the presence of elevated NEFA, and monounsaturated fatty acids promote insulin‐mediated cortical activity 52, 53.…”

Section: Central Nervous System Hypothesismentioning

confidence: 99%

Weight‐sparing effect of insulin detemir: a consequence of central nervous system‐mediated reduced energy intake?

Russell‐Jones

Danne

Hermansen

et al. 2015

Diabetes Obesity Metabolism

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Insulin therapy is often associated with adverse weight gain. This is attributable, at least in part, to changes in energy balance and insulin's anabolic effects. Adverse weight gain increases the risk of poor macrovascular outcomes in people with diabetes and should therefore be mitigated if possible. Clinical studies have shown that insulin detemir, a basal insulin analogue, exerts a unique weight‐sparing effect compared with other basal insulins. To understand this property, several hypotheses have been proposed. These explore the interplay of efferent and afferent signals between the muscles, brain, liver, renal and adipose tissues in response to insulin detemir and comparator basal insulins. The following models have been proposed: insulin detemir may reduce food intake through direct or indirect effects on the central nervous system (CNS); it may have favourable actions on hepatic glucose metabolism through a selective effect on the liver, or it may influence fluid homeostasis through renal effects. Studies have consistently shown that insulin detemir reduces energy intake, and moreover, it is clear that this shift in energy balance is not a consequence of reduced hypoglycaemia. CNS effects may be mediated by direct action, by indirect stimulation by peripheral mediators and/or via a more physiological counter‐regulatory response to insulin through restoration of the hepatic–peripheral insulin gradient. Although the precise mechanism remains unclear, it is likely that the weight‐sparing effect of insulin detemir can be explained by a combination of mechanisms. The evidence for each hypothesis is considered in this review.

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Fatty Acids, Obesity, and Insulin Resistance: Time for a Reevaluation

Cited by 715 publications

References 83 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

Metabolic flexibility and oxidative capacity independently associate with insulin sensitivity in individuals with newly diagnosed type 2 diabetes

Weight‐sparing effect of insulin detemir: a consequence of central nervous system‐mediated reduced energy intake?

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