Relation of adipose tissue to metabolic flexibility

https://doi.org/10.1016/j.diabres.2008.09.052Get rights and content

Abstract

Metabolic flexibility is the capacity for skeletal muscle to shift reliance between lipids and glucose during fasting or in response to insulin. We hypothesized that body fat, adipose tissue characteristics, e.g. larger adipocytes, presence of inflammatory gene markers and impaired suppression of non-esterified fatty acids (NEFAs) during insulin infusion might be related to metabolic flexibility.

We measured changes in respiratory quotient (ΔRQ) before and during euglycemic-hyperinsulinemic clamp in healthy young males. Body fat by DXA, laboratory measurements, abdominal subcutaneous adipose tissue biopsies and fat cell size (FCS) were obtained after an overnight fast. Gene expression for 17 adipose tissue genes related to lipid synthesis, uptake, oxidation and storage, lipolysis and inflammation were measured.

Reduced metabolic flexibility was associated with higher body fat, larger FCS and impaired insulin suppression of NEFAs. Metabolic flexibility was associated with higher serum adiponectin levels. Lower adipose tissue gene expression for inflammation markers was associated with greater NEFA suppression by insulin and metabolic flexibility.

Combined, these results indicate that body fat, larger adipocytes, failure of insulin to suppress NEFAs, decreased adiponectin levels and inflammation markers in adipose tissue are associated with decreased insulin-stimulated glucose uptake and oxidation, which is an important component of reduced metabolic flexibility.

Introduction

Metabolic flexibility is the capacity for skeletal muscle to acutely shift its reliance between lipids and glucose during fasting or in response to insulin, such as in postprandial conditions. Two fundamental features of reduced metabolic flexibility are decreased fat oxidation in the fasting state (i.e. higher respiratory quotient (RQ)) and decreased insulin-stimulated glucose oxidation. Another important feature of reduced metabolic flexibility is an impaired suppression of non-esterified free fatty acid (NEFA) release (lipolysis) in response to insulin [1]. Impaired insulin stimulation of glucose uptake by skeletal muscle [2], impaired skeletal muscle mitochondrial biogenesis and decreased capacity for oxidation of dietary fat are all involved in reducing metabolic flexibility [3]. Furthermore, these physiologic characteristics are enriched in healthy young men with a family history of type 2 diabetes (T2D) [4]. The cause of the derangements in skeletal muscle of type 2 diabetic patients remains to be elucidated. Impaired mitochondrial function is a likely candidate. Evidence from both in vivo and ex vivo studies supports the idea that an impaired skeletal muscle mitochondrial function is related to the development of insulin resistance and type 2 diabetes. A decreased mitochondrial oxidative capacity in skeletal muscle was revealed in diabetic patients, using in vivo 31-Phosphorus Magnetic Resonance Spectroscopy (31P-MRS) [5]. Insulin resistance is associated with metabolic inflexibility, impaired switching of substrate oxidation from fatty acids to glucose in response to insulin. Ukropcova et al. recently demonstrated that muscle mitochondrial content was higher in flexible subjects with high fat oxidation after a high fat diet (HFD) and contributed 49% of the variance. Subjects with a family history of diabetes were inflexible and had reduced HFD-induced fat oxidation and muscle mitochondrial content but did not differ in the amount of body or visceral fat. Metabolic inflexibility, lower adaptation to an HFD and reduced muscle mitochondrial mass cluster together in subjects with a family history of diabetes, supporting the role of an intrinsic metabolic defect of skeletal muscle in the pathogenesis of insulin resistance [4].

Fuel selection is a key component of insulin sensitivity. Skeletal muscle accounts for 80–90% of insulin-stimulated glucose disposal and is the primary tissue responsible for peripheral insulin sensitivity and glucose homeostasis [6]; however, the role of adipose tissue has been unexplored. White adipose tissue (WAT) is a major site of energy storage, and it is important for energy homeostasis. WAT stores energy in the form of triglycerides when in positive energy balance and releases energy as NEFAs when energy expenditure exceeds energy intake [7], [8]. While WAT provides a survival advantage in times of starvation, excess WAT and larger adipocytes are now recognized as links to the health problems associated with obesity of developed countries. Furthermore, while adipocytes are traditionally known as fat storage cells, adipose tissue is also an endocrine organ that secretes hormones, chemokines and cytokines. Increased basal/fasted lipolysis in white adipose tissue leads to increase fasting NEFA levels [9]. Increased chemotaxis and macrophage content in WAT are characteristics of the obese state. While there are very few manuscript that measure both body composition and adipose tissue gene expression, several of these are from our own group and no paper, to our knowledge, exists that compares inflammatory markers to high quality gene expression. One paper from our group demonstrated that the combined activation of peroxisome proliferator-activated receptor-gamma and beta-adrenergic receptors has beneficial effects on body weight, plasma triglycerides and lipid metabolism in subcutaneous fat by increasing the expression of genes required for fatty acid catabolism [10].

We hypothesized that the quantity and the characteristics of the adipose tissue (larger adipocytes, expression of macrophage genes and disordered fatty acid oxidation) might contribute to the state of reduced metabolic flexibility. To explore this hypothesis, we studied 56 healthy young men under carefully controlled conditions, examining how adipose tissue mass and fat cell size (FCS) influence metabolic flexibility during a euglycemic-hyperinsulinemic clamp (EHC).

Section snippets

Study population and design

All procedures were approved by the PBRC IRB board. After providing written informed consent, a cohort of 56 healthy young men, aged 22.6 ± 3.2 years with a BMI of 26.4 ± 4.1 kg/m2 underwent physical examination, medical laboratory tests and measurement of body fat by dual energy X-ray absorptiometry (DXA). Thirteen of the 56 healthy young men had a BMI > 30, but less than 35 kg/m2, and 16 of the 56 participants had a family history of T2D. These clinical characteristics were taken into account in the

Body fat, fat cell size and serum adiponectin are associated with metabolic flexibility (ΔRQ) in healthy young men

Subject characteristics are listed in Table 4. All subjects were sedentary healthy young men ranging widely in BMI (20.1–34.7 kg/m2) and percent body fat (8.4–32.3%). RQ was measured before and during the euglycemic-hyperinsulinemic clamp to determine metabolic flexibility (ΔRQ). ΔRQ varied greatly, but was normally distributed, ranging from inflexible (ΔRQ = 0.03) to flexible (ΔRQ = 0.25). We divided metabolic flexibility (ΔRQ) into quartiles (quartile 1 = ΔRQ < 0.06; quartile 2 = 0.06 < ΔRQ  0.08; quartile

Discussion

Metabolic flexibility (ΔRQ) is influenced by both skeletal muscle and adipose tissue. The contribution of skeletal muscle to metabolic flexibility is related to mitochondrial content and function [3], [19]. The aim of this study was to determine how adipose tissue might relate to metabolic flexibility. We found that metabolic flexibility is negatively associated with percent body fat, fat cell size and insulin-suppressed NEFAs; that is, those who were metabolically flexible were less fat, had

Conflict of interest

None.

Acknowledgments

This work was supported by USDA grant #2003-34323-14010 and USPHS grant HL67933. We also thank the study participants.

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