Effects of Moderate and Subsequent Progressive Weight Loss on Metabolic Function and Adipose Tissue Biology in Humans with Obesity

Abstract

Although 5%-10% weight loss is routinely recommended for people with obesity, the precise effects of 5% and further weight loss on metabolic health are unclear. We conducted a randomized controlled trial that evaluated the effects of 5.1% ± 0.9% (n = 19), 10.8% ± 1.3% (n = 9), and 16.4% ± 2.1% (n = 9) weight loss and weight maintenance (n = 14) on metabolic outcomes. 5% weight loss improved adipose tissue, liver and muscle insulin sensitivity, and β cell function, without a concomitant change in systemic or subcutaneous adipose tissue markers of inflammation. Additional weight loss further improved β cell function and insulin sensitivity in muscle and caused stepwise changes in adipose tissue mass, intrahepatic triglyceride content, and adipose tissue expression of genes involved in cholesterol flux, lipid synthesis, extracellular matrix remodeling, and oxidative stress. These results demonstrate that moderate 5% weight loss improves metabolic function in multiple organs simultaneously, and progressive weight loss causes dose-dependent alterations in key adipose tissue biological pathways.

Figure 1. Effect of 5% weight loss on subcutaneous adipose tissue gene expression of inflammatory markers

Subcutaneous abdominal adipose tissue expression of genes involved in inflammation was determined by real-time PCR before (black bars) and after (white bars) 5% weight loss (n = 19) or weight maintenance (n = 12). The effect of time (before vs. after) and differences between groups (weight maintenance vs. weight loss) were evaluated by using repeated measures analysis of variance. Significant time-by-group interactions were followed by appropriate within-and between-group post-hoc tests. Non-normally distributed variables were log transformed for analysis and back transformed for presentation. Data are means ± SEM. No effects of weight loss were detected. ^†P<0.05 vs. weight maintenance group before and after the intervention. Abbreviations: TNF, tumor necrosis factor; IL6, interleukin 6; MCP1, monocyte chemoattractant protein 1; RANTES, regulated on activation normal T cell expressed and secreted; CD68, cluster of differentiation 68; EMR1, EGF-like module-containing mucin-like hormone receptor-like 1.

Figure 2. Effect of progressive weight loss on subcutaneous adipose tissue gene expression profile

Parametric analysis of gene-set enrichment (PAGE) was performed on microarray data to identify biological pathways in subcutaneous abdominal adipose tissue that increased (red) or decreased (blue) with progressive weight loss in subjects with obesity (n = 9). Biological pathways that were significantly affected by 5%, 11%, or 16% weight loss, based on the Z score between baseline (before weight loss) and 16% weight loss (A). Biological pathways involved in regulating cholesterol flux were significantly up-regulated, and pathways involved in lipid synthesis, regulating extracellular matrix (ECM) remodeling, and oxidative stress were significantly down-regulated by progressive weight loss (B). Subcutaneous abdominal adipose tissue expression of genes involved in regulating cholesterol flux, synthesis, ECM remodeling, and oxidative stress was determined by real-time PCR before (0) and after progressive 5% (5), 11% (10), and 16% (15) weight loss (C). The main effect of time was evaluated with repeated measures analysis of variance, which revealed significant linear changes for all genes. Non-normally distributed variables were log transformed for analysis and back transformed for presentation. Data are means ± SEM. *P<0.05 vs. baseline; ^†P<0.05 for linear component and ^‡P<0.05 for quadratic component. Abbreviations: ABCG1, ATP-binding cassette sub-family G member 1; ABCA1, ATP-binding cassette transporter ABCA1; APOE, apolipoprotein E; CETP, cholesteryl ester transfer protein; SCD, stearoyl-CoA desaturase; FADS1, fatty acid desaturase 1; FADS2, fatty acid desaturase 2; ELOVL6, elongation of very long chain fatty acids protein 6; SPARC, secreted protein acidic and rich in cysteine; MFAP5, microfibrillar-associated protein 5; LOX, lysyl oxidase; LOXL2, lysyl oxidase homolog 2; ANGPT1, angiopoietin 1; ADAM12, disintegrin and metalloproteinase domain-containing protein 12; NQO1, NAD(P)H dehydrogenase, quinone 1; DHCR24, 24-dehydrocholesterol reductase; UCHL1, ubiquitin carboxyl-terminal esterase L1.