• In recent years, much progress has been made in understanding the complex metabolic and neurohormonal mechanisms that control body weight.

• Differences in adaptive thermogenesis, or the modulation of energy expenditure and heat generation during cold exposure, underfeeding, or overfeeding, might explain some of the observed inter-individual variation in response to weight loss.

• Brown adipose tissue (BAT) is the tissue responsible for adaptive thermogenesis, and cold-induced thermogenesis appears to increase in proportion to BAT activity.1

• BAT activity is significantly higher in lean than obese individuals, although it is not known whether this is a cause or a consequence of obesity.

• In one study, 10 obese patients who lost ~28% of their body weight after bariatric surgery had significant increases in BAT activity after 1 year.2 Similarly, a previous study of subjects in a 6-month lifestyle modification program who lost 3.5-24.5% (mean 12.5%) of their body weight showed a trend toward an increase in BAT activity, though the results did not reach statistical significance.3

• As a result, it is not known whether BAT activity increases with modest weight loss.

• Our study examined the effect on BAT activity in subjects after a 10% weight loss achieved through a very low calorie diet program.

• Additionally, there has been increasing interest about a potential association between the presence of active BAT and improved metabolic parameters, particularly glucose and insulin metabolism.4

• After depleting intracellular triglycerides, it is thought that activated BAT utilizes plasma glucose as well as fatty acids as energy sources. We therefore hypothesized that individuals with larger BAT depots might have improved metabolic health, regardless of weight.

Background

• Before weight loss, after controlling for adiposity, subjects with higher BAT activity tended to have higher HDL levels and leptin levels, lower triglyceride levels, and smaller waist circumferences.

• With active weight loss, there was not an increase in the prevalence of active BAT. This was expected due to the known suppressive effects of fasting on the sympathetic nervous system, which in turn regulates BAT activity.

• With weight stabilization at a 10% reduced body weight, there was a trend towards an increased prevalence of active BAT, though this was not significant in our small sample.

• Additional research is needed to elucidate the potential role of BAT in weight regulation and metabolic health.

Figure 1. BAT activity, as measured in units of SUVmax, of each subject (represented by each colored line) at visit 1, before weight loss, and again at visit 3, after maintaining a 10% reduced body weight for 2 weeks.

T-2299-P: The Effect of Weight Loss in Obesityon Brown Adipose Tissue

Lisa M. Neff, MD, MS1,2; Kirsi A. Virtanen, MD, PhD3; Mindy Hoffmann, MA2; Dinah Zeiss, MS1; Katherine Lowry4; Monica Edwards, MD, MPH2; Lewis Landsberg, MD1,2

1Northwestern Comprehensive Center on Obesity, Northwestern University, Feinberg School of Medicine, Chicago, IL. 2Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL. 3Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland.

4Department of Medicine, Southern Illinois University School of Medicine, Springfield, IL.

Table 1. Demographics of the study subjects.

Conclusions

Characteristic Mean (SEM) Range

Age (years) 49 (2) 23 - 64

BMI (kg/m2) 35.3 (0.79) 28 - 40

Number of subjects %

Gender

Male 11 58

Female 8 42

Ethnicity

Caucasian 12 63

African American 3 16

Hispanic 3 16

Asian 1 5

• We studied 19 overweight and obese (mean BMI 35.3 ± 3.4 kg/m2, range 28 - 40 kg/m2) men and postmenopausal women, ages 23 to 64. (See Table 1 for demographics of study subjects.)

• Subjects were admitted overnight in the Clinical Research Unit at Northwestern Memorial Hospital during three timepoints:

• Visit 1) before weight loss;• Visit 2) immediately after achievement of a 10% weight loss during

continued negative energy balance;• Visit 3) following two weeks of weight stability at a 10% reduced

body weight. • Weight loss was achieved using a standard very low calorie diet (800

kcal/day) over an average time course of 59 days (range 33-112 days). Weight stabilization was accomplished using packaged nutritional products at a calorie level deemed appropriate for weight maintenance, with daily caloric adjustment as needed.

• At each visit, testing included measurement of cold-activated BAT activity (18F-FDG PET-CT) in the morning after an overnight fast. Each subject wore standardized clothing and was exposed to mild cold (16° C) for two hours prior to PET-CT scan.

• Each visit also included measurement of resting energy expenditure (REE; by indirect calorimetry), body composition (DEXA), and fasting levels of lipids, glucose, insulin, hemoglobin A1c, total T3, free T4, and leptin. HOMA score was calculated using the HOMA2 Calculator program available from the University of Oxford.

• Data analyses were conducted using SPSS v. 22 (IBM). McNemar’s Chi-square test was used to assess the change in prevalence of BAT activity with weight loss. The association between metabolic parameters (such as HDL cholesterol) and BAT activity, after controlling for fat mass (or if appropriate, lean mass), was assessed using partial correlations.

Effect of Weight Loss on BAT:•A maximal standardized uptake value (SUVmax) of ≥ 2 g/mL was considered indicative of activated BAT. •Before weight loss, 3 of 19 subjects (15.8%) had active BAT. At visit 2, during active weight loss, one BAT- subject became BAT+ and one BAT+ subject became BAT-, so that 15.8% still had active BAT. At visit 3, at a reduced but stable weight, 6 of 19 subjects (31.6%) were BAT+, though this increase in BAT prevalence was not statistically significant. 4 of the 6 subjects who were BAT+ at visit 3 did not have BAT at visit 1. (See Fig. 1 for graph of changes in BAT activity in each subject between visit 1 and 3.)•SUVmax and SUVmean did not change significantly with weight loss. •Most subjects with significant changes in BAT activity were studied within a single season, so that ambient temperatures did not appear to play a significant role in the changes in BAT activity among our volunteers.

BAT and Biomarkers of Metabolic Health:•After controlling for fat mass, there was a significant positive association between HDL and SUVmax at visit 1, before weight loss (R=0.594, p=0.007) and a significant positive association between HDL and SUVmean at visit 1 (R=0.663, p=0.002) (See Fig. 2). Removal of one extreme outlier (who had both extremely high BAT activity and high HDL of 70 mg/dL at baseline) strengthened the associations further (R=0.689, p=0.002 for SUVmax and R=0.742, p<0.001 for SUVmean).•At visit 1, after controlling for fat mass, there was a nonsignificant trend for an association between leptin and SUVmean (R=0.414, p=0.078). Removal of the extreme outlier generated positive correlations at visit 1 between leptin and SUVmax (R=0.528, p=0.024) and leptin and SUVmean (R=0.503, p=0.033) (See Fig. 3).•After controlling for fat mass, there was a nonsignificant trend for a negative correlation between SUVmean and waist circumference at visit 1 (R = -0.454, p=0.058). Removal of the extreme outlier generated negative correlations at visit 1 between SUVmax and waist circumference (R=-0.502, p=0.040), SUVmean and waist circumference (R=-0.594, p=0.012), and SUVmax and triglyceride level (R=-0.469,p=0.049). (See Figs. 4 & 5).•Thus, after controlling for adiposity, BAT activity appears to explain about 35-40% of the remaining variation in HDL, 20% of the remaining variation in triglyceride levels, and about 20-35% of the remaining variation in waist circumference. In addition, BAT activity and leptin levels appear to be positively associated, even after controlling for adiposity.

Methods Results

1. Yoneshiro T, Aita S, Matsushita M, Kameya T, Nakada K, et al. Brown adipose tissue, whole-body energy expenditure, and thermogenesis in healthy adult men. Obesity 2011;19:13-16.

2. Vijgen GHEJ, Bouvy ND, Teule GJJ, Brans B, Hoeks J, Schrauwen P, et al. Increase in brown adipose tissue activity after weight loss in morbidly obese subjects. J Clin Endocrinol Metab 2012;97:E1229–1233.

3. Orava J, Nuutila P, Noponen T, Parkkola R, Viljanen T, Enerbäck S, et al. Blunted metabolic responses to cold and insulin stimulation in brown adipose tissue of obese humans. Obesity 2013;21:2279–87.

4. Chondronikola M, Volpi E, Børsheim E, Porter C, Annamalai P et al. Brown adipose tissue improves whole body glucose homeostasis and insulin sensitivity in humans. Diabetes 2014 Jul 23. pii: DB_140746.

ReferencesFigure 2 (Above). After controlling for fat mass, there was a significant positive association between HDL and SUVmax at visit 1, before weight loss (R = 0.594, p=0.007).Figure 3 (Left). Removal of an extreme outlier generated a positive correlation between leptin and SUVmax , after controlling for fat mass (R=0.528, p=0.024).

Figure 4 & 5 (Above). Removal of the extreme outlier generated negative correlations at visit 1 between SUVmax and triglyceride level (R=-0.469,p=0.049)and SUVmax and waist circumference (R=-0.502, p=0.040), after controlling for fat mass.