Ursula White

Background/Objectives: Limited information exists on how dietary patterns change in adults who experience weight regain vs. those who maintain weight loss after lifestyle interventions. Methods: Five hundred fifty-two adults (60 ± 1.0 years, 33.8 ± 0.4 kg/m²) with type 2 diabetes mellitus from the Look AHEAD Trial achieved ≥ 7% weight loss after Year 1, completed follow-up visits through Year 4, and provided three 134-item food frequency questionnaires. Weight “regain” (WLR) was defined as regaining ≥ 50% of the initial weight lost. Dietary patterns were determined using established DASH diet scores (scale: 0–9) and principal component analysis (PCA; higher scores = more adherent). Repeated measures linear mixed models assessed group and sex differences in dietary patterns. Results: Dietary patterns were similar between groups during weight loss (baseline to Year 1). WLR DASH scores decreased more from Year 1 to Year 4 compared to “maintain” (WLM) (WLR: Y1: 5.66 ± 0.14, Y4: 4.60 ± 0.14; WLM: Y1: 5.49 ± 0.13, Y4: 4.92 ± 0.13; difference-p < 0.01). Of the two PCA-derived dietary patterns, Pattern 1 (vegetable, fruit, and fish) decreased more in WLR (WLR: Y1: 0.12 ± 0.16, Y4: −0.14 ± 0.16, WLM: Y1: 0.06 ± 0.14, Y4: 0.25 ± 0.15; difference-p < 0.01), while Pattern 2 (low-fiber grains and high-fat animal proteins) increased in WLR (WLR: Y1: 0.40 ± 0.11, Y4: 0.61 ± 0.11, WLM: Y1: 0.34 ± 0.10, Y4: 0.21 ± 0.10, difference-p < 0.01). Sex differences showed that only WLR women and WLM men increased sweets from Y1 to Y4 (WLR women Y1: 0.26 ± 0.04, Y4: 0.41 ± 0.04; p < 0.01; WLM men: Y1: 0.23 ± 0.04, Y4: 0.38 ± 0.04; p < 0.01). Conclusions: These data demonstrate that differences in dietary patterns between WLR and WLM emerge after the initial weight loss intervention with some sex differences. This suggests that longer-term shifts in dietary patterns after lifestyle interventions may influence weight loss maintenance.

White adipose tissue is a highly plastic organ that is necessary to maintain whole-body energy homeostasis. The adipose tissue mass and changes in the fat mass or distribution are regulated by changes in the synthesis and breakdown (i.e., turnover) of adipose cells and triacylglycerols. Evidence suggests that the manner and magnitude of subcutaneous adipose tissue expansion (i.e., hypertrophy vs. hyperplasia) and turnover can influence metabolic health, as adipogenesis has been implicated in the pathogenesis of obesity and related diseases. Despite the potential role of adipose turnover in human health, there is a lack of knowledge about the in vivo kinetics of adipose cells. This is due, in part, to the slow turnover rate of the cells in adipose tissue and the practical complexity of directly labeling their metabolic precursors in vivo. Herein, we describe methods to measure in vivo adipose kinetics and turnover rates in humans through the consumption of deuterium (2H)-labeled water. The incorporation of 2H into the deoxyribonucleotide moieties of DNA in pre-adipocytes and adipocytes provides an accurate measure of cell formation and death (adipose turnover). Overall, this is an innovative approach to measuring in vivo adipose kinetics and represents a substantive departure from other in vitro assessments.

White adipose tissue (WAT) expands under physiological conditions via an increase in adipocyte size (hypertrophy) and/or number (hyperplasia; adipogenesis), and the ability of WAT to expand to accommodate energy demands is a significant determinant of metabolic health status. Obesity is associated with impaired WAT expansion and remodeling, which results in the deposition of lipids to other non-adipose organs, leading to metabolic derangements. Although increased hyperplasia has been implicated as a cornerstone in promoting healthy WAT expansion, recent developments suggest that the role of adipogenesis as a contributing factor in the transition from impaired subcutaneous WAT expansion to impaired metabolic health remains up for debate. This mini-review will summarize recent developments and highlight emerging concepts on the features of WAT expansion and turnover, and the significance in obesity, health, and disease.

Background Adipose tissue (AT) expansion occurs by hypertrophy (increase in size) and hyperplasia (increase in number) of adipocytes. The AT expandability hypothesis postulates that impaired subcutaneous AT expansion leads to ectopic fat accretion, contributing to impaired metabolic health. The role of adipogenesis as a contributing factor is debatable. Subjects/Methods In the present analysis, we assess changes in adipocyte size distribution in relation to changes in ectopic fat accretion in response to 8-weeks of overfeeding in 22 men (28 ± 5.4 years; BMI 25.5 ± 2.3 kg/m²) who were fed 40% over their baseline energy requirements. Results Participants gained 6.7 ± 2.1 kg. The percentage of small adipocytes (p = 0.03) and the peak diameter of large adipocytes (p = 0.01) increased after overfeeding. At baseline, the percentage of small adipocytes was positively correlated with % body fat (p = 0.03), SAT mass (p = 0.01), VAT mass (p = 0.02), VAT:TAT (p = 0.05), and IHL (p = 0.09; trend). The relative (percent) change in small adipocytes was positively associated with the increase in whole-body fat (p = 0.001), VAT mass (p = 0.0003), VAT:TAT (p = 0.01), and IHL (p = 0.007) in response to overfeeding. Conclusions These findings, surprisingly, indicate that during substantial weight gain, an increase in small adipocytes (suggesting hyperplastic expansion) is associated with impaired (not improved) metabolic health outcomes, specifically visceral and ectopic fat accumulation. Clinical trial registration ClinicalTrials.gov Identifier- NCT01672632.

Obesity, insulin resistance, and type 2 diabetes contribute to increased morbidity and mortality in humans. The db/db mouse is an important mouse model that displays many key features of the human disease. Herein, we used the drug pioglitazone, a thiazolidinedione with insulin-sensitizing properties, to investigate blood glucose levels, indicators of islet β-cell health and maturity, and gene expression in adipose tissue. Oral administration of pioglitazone lowered blood glucose levels in db/db mice with a corresponding increase in respiratory quotient, which indicates improved whole-body carbohydrate utilization. In addition, white adipose tissue from db/db mice and from humans treated with pioglitazone showed increased expression of glycerol kinase. Both db/db mice and humans given pioglitazone displayed increased expression of UCP-1, a marker typically associated with brown adipose tissue. Moreover, pancreatic β-cells from db/db mice treated with pioglitazone had greater expression of insulin and Nkx6.1 as well as reduced abundance of the de-differentiation marker Aldh1a3. Collectively, these findings indicate that four weeks of pioglitazone therapy improved overall metabolic health in db/db mice. Our data are consistent with published reports of human subjects administered pioglitazone and with analysis of human adipose tissue taken from subjects treated with pioglitazone. In conclusion, the current study provides evidence that pioglitazone restores key markers of metabolic health and also showcases the utility of the db/db mouse to understand mechanisms associated with human metabolic disease and interventions that provide therapeutic benefit.

Exercise has beneficial effects on metabolism and health. Although the skeletal muscle has been a primary focus, exercise also mediates robust adaptations in white adipose tissue. To determine if exercise affects in vivo adipocyte formation, fifty-two, sixteen-week-old C57BL/6J mice were allowed access to unlocked running wheels [Exercise (EX) group; n = 13 males, n = 13 females] or to locked wheels [Sedentary (SED) group; n = 13 males, n = 13 females] for 4-weeks. In vivo adipocyte formation was assessed by the incorporation of deuterium (²H) into the DNA of newly formed adipocytes in the inguinal and gonadal adipose depots. A two-way ANOVA revealed that exercise significantly decreased new adipocyte formation in the adipose tissue of mice in the EX group relative to the SED group (activity effect; P = 0.02). This reduction was observed in male and female mice (activity effect; P = 0.03). Independent analysis of the depots showed a significant reduction in adipocyte formation in the inguinal (P = 0.05) but not in the gonadal (P = 0.18) of the EX group. We report for the first time that exercise significantly reduced in vivo adipocyte formation in the adipose tissue of EX mice using a physiologic metabolic ²H₂O-labeling protocol.

Aims/hypothesis In vitro and rodent studies suggest that pioglitazone, a thiazolidinedione, can promote adipogenesis in adipose tissue (AT); however, there is a lack of in vivo studies in humans to support these findings. The objectives of this randomised, placebo-controlled, parallel-arm trial were to test if pioglitazone stimulates in vivo adipogenesis in the subcutaneous adipose tissue depots and if these measures were related to metabolic health outcomes in women with obesity. Methods Forty-one healthy women with obesity (20 black; 21 white; 29 ± 6 years; BMI 32.0 ± 1.7 kg/m²; 44.0 ± 3.6% body fat) were randomised to consume 30 mg/day of pioglitazone (n = 21) or placebo (n = 20) for 16 weeks. SAS v9.4 was used to generate the block randomisation code sequence (stored in password-protected files) with a 1:1 allocation ratio. The participants and study staff involved in assessing and analysing data outcomes were blinded to the group assignments. The trial was conducted at Pennington Biomedical Research Center and ended in 2016. At baseline and post-intervention, subcutaneous abdominal (scABD) and femoral (scFEM) AT biopsies were collected, and in vivo cellular kinetics (primary endpoint of the trial) were assessed by an 8 week labelling protocol of deuterium (²H) into the DNA of adipose cells. Body composition was measured by dual-energy x-ray absorptiometry (DXA), scABD and visceral AT (VAT) by MRI, ectopic fat by ¹H-MRS, and insulin sensitivity by an OGTT. Results After the 16 week intervention, there was a significant decrease in visceral fat (VAT:total abdominal AT [as a %]; p = 0.002) and an increase in the Matsuda index (i.e. improved insulin sensitivity; p = 0.04) in the pioglitazone group relative to the placebo group. A significant increase in the formation of new adipocytes was observed in the scFEM (Δ = 3.3 ± 1.6%; p = 0.04) but not the scABD depot (Δ = 2.0 ± 2.1%; p = 0.32) in the pioglitazone group relative to the placebo group. No serious adverse events were reported. Conclusions/interpretation Pioglitazone may elicit distinct differences in in vivo adipogenesis in subcutaneous adipose depots in women with obesity, with increased rates in the protective scFEM. Trial registration ClinicalTrials.govNCT01748994 Funding This study was funded by R01DK090607, P30DK072476, and R03DK112006 from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. U54 GM104940 from the National Institute of General Medical Sciences of the National Institutes of Health. The Robert C. and Veronica Atkins Foundation. Graphical abstract

Alcohol (i.e., ethanol) is consumed regularly by much of the adult population; yet, the health effects associated with its use are not well-characterized. Clinical interventions to investigate the effects of moderate alcohol consumption on metabolic outcomes, including adiposity and cardiovascular risk factors, are limited and have yielded conflicting data. In addition, no study has reported the effects of routine alcohol intake during weight loss in a controlled feeding trial. We present the first randomized controlled pilot trial to investigate the effects of moderate alcohol consumption on metabolic outcomes during weight loss in women with obesity. Both groups consumed 30% energy restricted diets and were randomized to either an ethanol-free control (CTL) group or a group (EtOH) that consumed 35 g ethanol daily for eight weeks. Our findings demonstrate that, despite similar weight loss, the decrease in mean arterial pressure was attenuated in the EtOH group, relative to the CTL group (p = 0.02). In addition, decreases in other outcomes, including visceral adipose tissue (p = 0.23), circulating lipids (triglycerides (p = 0.11) and cholesterol (p = 0.11)), and uric acid (p = 0.07) tended to be attenuated with alcohol consumption. These pilot data provide potential evidence that moderate alcohol consumption may mitigate the beneficial effects of weight loss and support the need for larger Randomized Controlled Trials (RCTs) to better investigate the metabolic effects of moderate alcohol intake in humans.

African Americans (AAs) have a higher obesity risk than Whites; however, it is unclear if appetite-related hormones and food intake are implicated. We examined differences in appetite-related hormones, appetite, and food intake between AAs (n = 53) and Whites (n = 111) with overweight or obesity. Participants were randomized into a control group or into supervised, controlled exercise groups at 8 kcal/kg of body weight/week (KKW) or 20 KKW. Participants consumed lunch and dinner at baseline and follow-up, with appetite and hormones measured before and after meals (except leptin). At baseline, AAs had lower peptide YY (PYY; p < 0.01) and a blunted elevation in PYY after lunch (p = 0.01), as well as lower ghrelin (p = 0.02) and higher leptin (p < 0.01) compared to Whites. Despite desire to eat being lower and satisfaction being higher in AAs relative to Whites (p ≤ 0.03), no racial differences in food intake were observed. Compared to Whites, leptin increased in the 8 KKW group in AAs (p = 0.01), yet no other race-by-group interactions were evident. Differences in appetite-related hormones between AAs and Whites exist; however, their influence on racial disparities in appetite, food intake, and obesity within this trial was limited.