Applied nutritional investigationCentral obesity and altered peripheral adipose tissue gene expression characterize the NAFLD patient with insulin resistance: Role of nutrition and insulin challenge
Introduction
Obesity, insulin resistance (IR) and fatty liver cluster together in the same individuals. The metabolic syndrome (MetS) concept integrates these pathologies [1]. The clinical relevance of the nonalcoholic fatty liver disease (NAFLD) derives mostly from its high prevalence in the general population (approximately10–24%), its associated risk for progression to nonalcoholic steatohepatitis (NASH), hepatic fibrosis, and cirrhosis (approximately 3%) [2]. The link between NAFLD and the rest of manifestations of the MetS are unclear but there is evidence that increased alanine aminotransferase (ALT) and γ-glutamyltransferase (GGT) levels are associated with both systemic and hepatic IR [3], [4], predict the development of type 2 diabetes mellitus (T2DM) and increased risk for cardiovascular diseases [5], [6]. Although the pathogenesis of NAFLD remains elusive, its association with obesity, dysfunctional adipose tissue (AT), IR, and specific nutritional patterns suggests they may share common pathogenic mechanisms [7]. Many obese patients develop NAFLD and IR [8]. The hallmark feature of NAFLD occurs when the rate of hepatic fatty acid uptake from plasma and de novo fatty acid synthesis are greater than the rate of fatty acid oxidation and export [9]. In these patients, there is increasing evidence that the dysfunction of the AT, and more specifically a lower disposal and storage of fatty acids and increased lipolysis by peripheral AT and dysfunctional pattern of adipocytokine secretion (e.g., decreased adiponectin, increased leptin [LEP], tumor necrosis factor [TNF] -α and interleukin [IL]-6), may directly contribute to the development of NAFLD and hepatic IR. However, not all obese individuals develop necessarily metabolic complications, as some remain insulin sensitive (IS) and do not develop fatty liver. On top of all these factors, the link between obesity and associated metabolic abnormalities seems to be related to the topography, anatomical distribution, and/or the functional peculiarities of the AT, a phenomenon that seems to be more relevant in patients with relatively normal weight [10].
In this study, we focused on molecular markers characteristically involved in the process of white adipose tissue (WAT) expansion. Specifically, we analyzed the transcription of LEP given its important effects in the control of energy balance and nutrient partitioning, but also because LEP promotes fatty acid oxidation exerting an antilipotoxic effect that prevents the development of fatty liver [11], [12], [13], [14]. The importance of the AT controlling energy homeostasis is further illustrated in patients with severe congenital or acquired lipodystrophy, where a decreased capacity of fat storage in peripheral adipocytes associated with IR, the excessive circulating fatty acids are forced to be deposited in liver and other metabolically relevant tissues. Additionally, these patients have low LEP levels which cannot exert its proxidative and antilipotoxic effects to prevent the development of fatty liver [15].
Environmental factors also play an important pathogenic role in NAFLD. Dietary treatments with a low-fat high-carbohydrate (CHO) diet intake are associated with postprandial hyperglycemia, hyperinsulinemia, and hypertriglyceridemia [16], as well as obesity, T2DM, NAFLD, and other manifestations of the MetS [17], [18]. Additionally, there is evidence that high fat diets (monounsaturated fatty acid [MUFA]- and saturated fatty acid [SAT]-rich) may increase the storage capacity of fat in WAT, while it decreases the central fat deposition compared with an isocaloric CHO-rich diet in insulin-resistant individuals [19]. However, in mice fed fat-rich diets (SAT and MUFA), the ratio of subcutaneous to visceral fat was significantly lower compared with mice fed low-fat diets, associated with the highest serum LEP levels [20]. Thus, here we characterized the transcriptional changes in the AT of NAFLD patients as a function of their IR status, and the AT transcriptional acute response to specific dietary treatments and insulin treatments in a subset of patients with the highest IR. This information will be helpful to provide evidence for specific dietary therapeutic approaches, before or in addition to pharmacologic interventions.
Section snippets
Study design
Participants were recruited from the endocrinology and gastroenterology services in University Hospital Reina Sofia of Cordoba (UHRS, Spain). The diagnosis of hepatic steatosis was made by hepatic ultrasonography [21]. Seventy-five consecutive patients with potential clinical inclusion criteria were recruited between 2007 and 2009, and invited to attend a screening session in order to determine their eligibility for the study. Clinical Inclusion criteria were as follows: A positive diagnosis of
Baseline participants’ characteristics
The study group was comprised of 20 men and 25 women and the mean (± SD) age was 45.7 ± 11.1. Mean fasting serum glucose concentrations were 5.45 ± 0.18 mmol/L, fasting serum insulin 104.9 ± 7.65 pmol/L and HbA1c concentration was 5.96 ± 0.1% (Table 1). The mean arterial blood pressure was 100 ± 1.72 mm Hg and HOMA-IR was 3.68 ± 0.29. After 2 h of an OGTT, serum glucose rose to 9.3 ± 0.5 mmol/L, plasma insulin concentration was 905 ± 94 pmol/L and the resulting ISi was 6.12 ± 0.42. The patients
Discussion
NAFLD is typically associated with other manifestations of the MetS such as IR and obesity and is affected by specific nutritional patterns. Here we have analyzed the clinical and specific metabolic profiles associated with NAFLD and established their association with a comprehensive gene-expression profile in WAT in patients with a recent diagnosis of NAFLD grouped according to their IR status.
Our first question was whether IR was associated with a greater degree of NAFLD at diagnosis. Our
Acknowledgments
The authors acknowledge the Spanish Arteriosclerosis Foundation (Award FEA/SEA 2008 to JAP: Basic research 2008); the Spanish Endocrinology and Nutrition Foundation (FSEEN, Award Lilly Obesity and Metabolic syndrome research to JAP, 2008). None of the authors had any financial or personal interest in any company or organization sponsoring the research. In memoriam to Dr. Jose Maria Latre, chief of Nuclear medicine service HURS and investigator for this project who died while he worked in our
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Cited by (0)
JAP was involved with the study concept and design, population selection, acquisition of data, analysis and interpretation of data, drafting of the manuscript, and final approval. AV-P was involved with study concept and design, analysis and interpretation of data, critical revision of the manuscript, and final approval. JME-M and DG-C contributed equally to the article. The authors declared no conflict of interest.