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. Author manuscript; available in PMC: 2023 Jul 1.
Published in final edited form as: Nutr Metab Cardiovasc Dis. 2022 Apr 12;32(7):1725–1733. doi: 10.1016/j.numecd.2022.04.006

Effect of physical activity in a weight loss program on circulating total ANGPTL8 concentrations in northern Americans with obesity: a prospective randomized controlled trial

Chia-Po Fu a,b,c, Elizabeth E Oczypok d, Hira Ali d, James P DeLany e, Valerie L Reeves f, Ruey-Feng Chang a, Erin E Kershaw d,*
PMCID: PMC9233128  NIHMSID: NIHMS1798009  PMID: 35527126

Abstract

Background and Aims:

The primary goals of this study were to clarify 1) the effect of weight loss by lifestyle intervention on circulating total angiopoietin-like protein 8 (ANGPTL8), and 2) the role of physical activity on serum total ANGPTL8 in northern Americans with obesity but without diabetes.

Methods and Results:

A total of 130 subjects with body mass index (BMI) ≧ 35 kg/m2 but without diabetes were recruited, and 121 subjects completed a weight loss program for data analysis. Abdominal adipose tissue was determined by non-contrast computed tomography (CT). Serum total ANGPTL8 was higher in the group with obesity than in the lean control group. Serum total ANGPTL8 was positively correlated with waist circumference (WC), BMI, fasting insulin, HOMA-IR, HOMA-B, QUICKI, hs-CRP, IL-6, and leptin. Serum total ANGPTL8 did not significantly differ between the two intervention groups at baseline, and it was significantly lower after weight loss, with comparable changes with diet only and diet plus physical activity.

Conclusion:

Among northern Americans with obesity but without diabetes, a lifestyle modification resulted in significant reduction of circulating total ANGPTL8 concentrations in a 6-month weight-loss period. Although addition of physical activity resulted in greater total and liver fat loss, it did not promote further significant decline of serum total ANGPTL8 beyond diet alone.

Keywords: ANGPTL8, weight loss, physical activity

1. Introduction

Obesity is a global public health problem worldwide and in the United States, where its prevalence is reported to be 35% and 40% in men and women, respectively [1, 2]. Obesity is highly associated with multiple metabolic abnormalities including insulin resistance, diabetes mellitus (DM), dyslipidemia, hypertension, and cardiovascular disease [3–5]. Proteins secreted by metabolically-relevant tissues, i.e. adipose tissue (“adipokines”) and liver (“hepatokines”), play critical roles in maintaining metabolic homeostasis and are frequently dysregulated in the context of obesity[6, 7]. Understanding the mechanism of action and physiological relevance of these secreted proteins is important for identifying novel metabolic markers and/or therapeutic strategies for obesity and associated metabolic disorders. Moreover, effects of weight loss with lifestyle intervention (diet or diet plus physical activity) are pivotal to clarify the roles of these proteins.

Angiopoietin-like protein 8, [ANGPTL8, alternatively designated as lipasin, refeeding-induced fat and liver (RIFL), hepatocellular carcinoma-associated protein TD26, and betatrophin] is a novel secreted protein encoded by the Angptl8 gene in mice (ANGPTL8 gene in humans) that has been implicated in both lipid and glucose homeostasis in murine models [8–12]. ANGPTL8 is expressed and secreted by liver and, to a lesser extent, adipose tissue, and is highly regulated by nutritional status (suppressed by fasting and induced by re-feeding) in both mice and humans [8–10, 12, 13]. Consistent with the homology of ANGPTL8 to members of the angiopoietin-like protein family [14], early metabolic studies of this protein in mice revealed that it influences serum triglycerides, in part by cleaving/activating ANGPTL3 and reducing lipoprotein lipase (LPL) activity [9, 12, 15]. In addition, ANGPTL8 also reduces lipogenesis in human hepatocytes exposed to lipotoxic conditions [16]. Interestingly, ANGPTL8 was subsequently independently identified as a protein that promotes pancreatic beta cell proliferation and mass expansion in response to obesity and insulin resistance [8]. Although a more recent study has suggested that these beta cell “trophic” effects may not apply to human beta cells [17], the above findings have nonetheless generated tremendous interest regarding the therapeutic potential of modulating ANGPTL8 in the treatment of obesity-associated metabolic diseases including dyslipidemia and diabetes [18–20].

Naturally, since these initial reports in murine models, a handful of studies have evaluated the relationship between serum ANGPTL8 and metabolic phenotypes in humans [13, 21–26]. Based on the proposed mechanism of action in mice, serum ANGPTL8 would be expected to be positively correlated with obesity, insulin resistance, and serum triglycerides [27]. Surprisingly, however, studies in humans have demonstrated considerable variability, with results that are often inconsistent with the above hypotheses and observations in mice [13, 21–25]. While this variability may be related to differences in study populations and/or experimental conditions, a previous report has suggested that these difference may instead be related to the species of ANGPTL8 being measured [28]. Specifically, ANGPTL8 may undergo proteolytic cleavage and differential degradation of its N- and C-terminal fragments [29]. Since the majority of human studies to date have measured N-terminal ANGPTL8 [21–23, 30, 31], this raises the possibility that total or C-terminal ANGPTL8 may be more biologically relevant in humans. Furthermore, since ANGPTL8 has been associated with obesity, it may be regulated by weight loss [32, 33]. Recent studies have shown contradictory results with regard to ANGPTL8 and weight loss [34–37], challenging ANGPTL8’s role as a regulator of obesity.

Thus, we aimed to clarify 1) the effect of weight loss by lifestyle intervention (diet or diet plus physical activity) on circulating total ANGPTL8 and 2) the role of physical activity on circulating total ANGPTL8 in a cohort of northern Americans with obesity but without diabetes.

2. Methods

2.1. Study subjects

This was a retrospective analysis of a prospectively -collected cohort of participants enrolled in a weight loss trial for severe obesity. Subjects were recruited by the Endocrine Metabolic Research Center (Department of Medicine) and the Physical Activity and Weight Management Research Center (Department of Health and Physical Activity) at the University of Pittsburgh as part of the Reenergize with Nutrition and Weight Loss Study (RENEW, ClinicalTrials.gov trial registration identifier: NCT00712127)[38]. A total of 130 subjects with BMI greater than or equal to 35 kg/m2 but with diabetes (see below) were recruited from the general population via television advertisement and mass mailing at University of Pittsburgh Medical Center from February 2007 to March 2009. Furthermore, 29 healthy and normal weight subjects with a BMI less than 24 kg/m2 served as a lean control group and did not receive any intervention. Subjects reported being relative healthy and were able to walk for 4 blocks without assistance. Subjects with a history of coronary artery disease, diabetes mellitus, uncontrolled hypertension, pregnancy within 6 months and diagnosis of cancer within 5 years of enrollment were excluded. Subjects did not have diabetes for the duration of the study based the following criteria: 1) no history of diabetes by self-report, 2) not taking diabetes medication by self-report, and 3) not having a fasting plasma glucose of >125 mg/dL (measured by the study). The ethics committee of the University of Pittsburgh approved the study and all subjects provided written informed consent.

2.2. Weight loss program

Subjects with obesity were randomized into two weight loss intervention groups, diet only (D) or diet plus physical activity (D+PA), with blocking according to sex, race, and level as obesity as previously described [38]. During the 6-month weight loss intervention, subjects were instructed with a combination of group and individual contacts. During this period, subjects were delivered with 3 group meetings and 1 individual contact per month. Subjects in both groups were prescribed a reduced calorie diet from 1200 to 2100 kcal/day based on their initial body weight. The hypo-caloric diet consisted of 50–55% carbohydrates, 20–30% fat, and 20–25% protein. Subjects were asked to keep a very detailed record of each meal to ensure the adherence of dietary intervention. Physical activity was prescribed as a moderate-intensity physical activity program to the D+PA group, such as brisk walking that progressed to 60 minutes for 5 days per week. Multiple 10-minutes sessions of physical activity were allowed, and self-monitored daily activity was recorded in a diary. Multisensor physical activity monitors (Sensewear Pro3; BodyMedia, Pittsburgh, Pennsylvania) were worn for 7 to 11 consecutive days to assess steps per day.

2.3. Laboratory investigation and body composition measurement

Subjects underwent blood testing following a 12-hour overnight fast. Blood samples were collected for measurements of glucose, insulin, lipid profile, liver enzymes, creatinine, high sensitivity c-reactive protein (hs-CRP), interleukin 6 (IL-6), adiponectin and leptin. Homeostatic model assessment-insulin resistance (HOMA-IR) was calculated as the blood glucose concentration (mmol/L) x the plasma insulin concentration (mU/L)/22.5[39]. Homeostatic model assessment-B cell function (HOMA-B) was calculated as ((20 × insulin (mU/L))/(glucose (mmol/L) − 3.5)) [39]. The quantitative insulin-sensitivity check index (QUICKI) was calculated as 1/[(log(plasma insulin in mU/L)+log(plasma glucose in mg/dL))] [40]. Serum total ANGPTL8 (including full-length and C-terminal fragments) was measured using ELISA (Phoenix Pharmaceuticals, #EK-051–60, Burlingame, CA) in previously unthawed samples [41]. The intra- and inter-assay CVs for ANGPTL8 were < 10% and < 15%, respectively. Body fat and fat-free mass (FFM) were determined by either dual-energy x-ray absorptiometry (DXA) in the majority of participants or by plethysmography in the 20 participants exceeding the weight limitation of the DXA scanner (>136kg). Abdominal adipose tissue and liver-spleen ratio were quantified by non-contrast computed tomography as previously described [42].

2.4. Statistical analysis

Continuous variables are expressed as mean±standard deviation (SD) and categorical data as number and percentages. Differences of continuous variables were compared by the Kruskal-Wallis analysis of variance test and the non-parametric Mann-Whitney test, and categorical data were compared by Chi-square test. The correlation between serum ANGPTL8, inflammatory markers (hs-CRP and IL-6), and other anthropometric parameters were determined by bivariate Pearson’s coefficients. Mixed model repeated measures were used to estimate the treatment effect of physical activity on ANGPTL8 changes over 6 months. Results were considered statistically significant at two-tailed P values of < 0.05. Data were analyzed using SAS software (version 9.4; SAS Institute, Inc., Cary, NC, USA).

3. Results

3.1. Characteristics of subjects before and after weight loss

A total of 130 subjects with obesity were initially screened for inclusion and of these, 9 subjects were excluded due to incomplete data for analysis. Of the 121 subjects, 62 subjects and 59 subjects were randomly allocated to D+PA or D only, respectively. Baseline characteristics of the D+PA and D were similar (Table 1). In addition, 29 normal weight, healthy subjects with a BMI less than 24 kg/m2 but without any intervention served as a lean control group for comparison of the baseline characteristics (Table 1 and Table 2). On average, participants were 47 years old with a BMI of 43 kg/m2 in the intervention group. Serum total ANGPTL8 was higher in the group with obesity than in the lean control group (2.55±2.10 vs. 1.43±1.91 ng/mL, P=0.01; data not shown). Serum ANGPTL8 did not differ between men and women in the control or intervention groups (Table 2). In addition, smoking rate was higher in the lean control group. There was no significant difference in fasting plasma glucose among the 4 groups; however, fasting insulin, HOMA-IR, HOMA-B, and QUICKI were significantly different among the 4 groups (Table 2) consistent with greater insulin resistance in the group with obesity.

Table 1.

Baseline characteristics among lean control group, Diet+PA group and Diet only group

Lean controls (N=29) Diet+PA (N=62) Diet (N=59)
Age, y/o 43±7 46±7 48±6
Male, n(%) 6 (20.7) 10 (16.1) 5 (8.5)
Race, Caucasian, n (%) 23 (79.3) 39 (62.9) 37 (62.7)
Smoker, n (%) 7 (24.1) 8 (12.9) 3 (5.1)
Blood pressure-lowering medication
 Angiotensin converting enzyme inhibitor 0 4 (6.5) 9 (15.3)
 Angiotensin receptor blocker 0 9 (14.5) 5 (8.5)
 Calcium channel blocker 0 3 (4.8) 6 (10.2)
 Thiazide diuretics 0 7 (11.3) 16 (27.1)
 Beta-blocker 0 4 (6.5) 5 (8.5)
 Other 0 3 (4.8) 5 (8.5)
 Total 0 20 (32.3) 23 (39.0)
Lipid lowering medication
 Statin 0 2 (3.2) 5 (8.5)
 Fibrate 0 1 (16) 1 (17)
 Fish oil 0 1 (16) 0
 Ezetimibe 0 0 1 (17)
 Total 0 4 (6.5) 7 (11.9)
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PA: physical activity.

Table 2.

Baseline characteristics between lean control group and obese group

Lean controls (n=29) Obese (n=121) P for difference
Man (n=6) Woman (n=23) Man (n=15) Woman (n=106)
Age, y/o 47±3 42±8 46±7 47±6 0.051
Race, Caucasian, n(%) 2 (33.3) 19 (82.6)* 11 (73.3) 69 (65.1) 0.025
ANGPTL8, ng/mL 1.64±0.38 1.38±2.15 2.00±1.36 2.62±2.20 0.003
Weight, kg 68.9±8.9 59.3±6.8* 126.9±19.8 116.5±15.7* <0.001
BMI, kg/m2 21.7±1.4 21.9±1.2 43.5±5.6 43.5±5.3 <0.001
FPG, mg/dL 95±6 91±5 96±12 93±11 0.394
Fins, mU/L 3.6±1.4 3.9±1.7 22.2±13.0 15.5±8.5 <0.001
HOMA-IR 0.81±0.36 0.84±0.38 5.10±2.49 3.62±2.22 <0.001
HOMA-B, % 39±19 52±26 301±280 220±120 <0.001
QUICKI 0.41±0.05 0.41±0.05 0.31±0.02 0.33±0.03 <0.001
WC, cm 78.6±17.5 74.9±6.3 134.2±13.7 121.0±11.3* <0.001
ALT, U/L 27±28 17±7 40±8 29±8* <0.001
Creatinine, mg/dL 0.94±0.15 0.74±0.12* 1.00±0.16 0.81±0.14* <0.001
SBP, mmHg 116±15 111±15 135±12 135±14 <0.001
HDL-C, mg/dL 54±17 58±12 41±6 49±11* <0.001
TG, mg/dL 49±10 71±33 153±78 121±60 <0.001
IL-6, pg/mL 1.69±2.60 1.53±2.12 2.71±1.76 2.70±1.83 <0.001
hs-CRP, mg/L 1.1±1.7 1.8±3.4 7.1±6.8 8.8±7.9 <0.001
Leptin, ng/mL 1.47±0.95 7.91±3.99* 31.4±17.5 57.2±22.7* <0.001
Adiponectin, pg/mL 8882±5749 11117±7895 5033±3319 6605±4524 0.028
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ANGPTL8: Angiopoietin-like protein 8; BMI: body mass index; FPG: fasting plasma glucose; Fins: fasting insulin; HOMA-IR: Homeostatic model assessment-insulin resistance; HOMA-B: Homeostatic model assessment-insulin resistance-beta cell function; QUICKI: quantitative insulin-sensitivity check index; WC: weight circumference; ALT: alanine aminotransferase; SBP: systolic blood pressure; HDL-C: high-density lipoprotein-cholesterol; TG: triglycerides; IL-6: interleukin 6; hs-CRP: high sensitivity c-reactive protein.

*

P value between man and woman using the non-parametric Mann-Whitney test, and P < 0.0125 was defined as significant difference

P for difference among the 4 groups using the Kruskal-Wallis analysis of variance test

3.2. Relationship of circulating total ANGPTL8 and anthropometric, serum, and imaging parameters

Baseline serum total ANGPTL8 was associated with WC, BMI, fasting insulin, HOMA-IR, HOMA-B, QUICKI, hs-CRP, IL-6 and leptin, but not age, ALT, creatinine, TG or FPG (Table 3). In addition, total ANGPTL8 concentrations were associated with liver fat, but not abdominal visceral adipose tissue, abdominal subcutaneous adipose tissue, total fat mass, fat-free mass or daily steps (Table 3).

Table 3.

Bivariate Pearson’s correlation between ANGPTL8 and anthropometric indices and daily steps

r P
Age, y/o 0.007 0.912
WC, cm 0.180 0.005
BMI, kg/m2 0.206 0.001
FPG, mg/dL 0.015 0.818
Fins, mU/L 0.164 0.011
HOMA-IR 0.173 0.008
HOMA-B, % 0.128 0.049
QUICKI −0.180 0.005
ALT, U/L 0.095 0.142
Creatinine, mg/dL −0.057 0.381
HDL-C, mg/dL −0.059 0.367
TG, mg/dL 0.018 0.779
hs-CRP, mg/L 0.178 0.006
IL-6, pg/mL 0.171 0.008
Leptin, ng/mL 0.131 0.044
Adiponectin, pg/mL 0.076 0.242
L/S ratio, HU −0.210 0.021
ABDVIS, cm2 0.092 0.315
ABDSUB, cm2 0.101 0.270
FM, kg 0.027 0.768
FFM, kg −0.129 0.258
Daily steps, steps 0.036 0.658
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ANGPTL8: Angiopoietin-like protein 8; WC: weight circumference; BMI: body mass index; FPG: fasting plasma glucose; Fins: fasting insulin; HOMA-IR: Homeostatic model assessment-insulin resistance; HOMA-B: Homeostatic model assessment-insulin resistance-beta cell function; QUICKI: quantitative insulin-sensitivity check index; ALT: alanine aminotransferase; HDL-C: high-density lipoprotein-cholesterol; TG: triglycerides; hs-CRP: high sensitivity c-reactive protein; IL-6: interleukin 6; L/S ratio: liver-to-spleen ratio; HU: Hounsfield unit; ABDVIS: abdominal visceral adipose tissue; ABDSUB: abdominal subcutaneous adipose tissue; FM: fat mass; FFM: fat-free mass

3.3. Treatment effect between diet plus physical activity versus diet only

Both D and D+PA were effective in promoting loss of weight and adiposity as well as improving metabolic parameters (Table 4). D+PA was slightly and significantly more effective than D alone at improving weight, BMI, WC, fat mass, liver-to-spleen ratio. Consistent with a potential role for ANGPTL8 in these phenotypes, serum ANGPTL8 was similar across groups at baseline (2.27±2.03 vs. 2.38±1.97, P=0.757) but was significantly lower after D+PA (0.51±0.27, P < 0.001) or D (0.61±0.24, P < 0.001) weight loss intervention compared to baseline. However, ANGPL8 did not differ between D+PA and D groups after the 6 month weight loss intervention (−1.8 vs. −1.82, P for interaction=0.969).

Table 4.

Baseline and 6-month differences between groups

univariable multivariable
ANGPTL8, ng/mL Baseline P a 6-months % change 6-months P b Treatment effect, univariable 95% confidence limits Pc for interaction Treatment effect, multivariable 95% confidence limits Pc for interaction
 Lean control 1.43±1.91
 Diet+PA 2.27±2.03 0.757 0.51±0.27 −1.76±2.08 <.0001 −1.77 −2.26 −1.28 0.971 −1.80 −2.33 −1.27 0.969
 Diet 2.38±1.97 0.61±0.24 −1.96±2.13 <.0001 −1.77 −2.27 −1.26 −1.82 −2.34 −1.29
Weight, kg
 Lean control 61.9±7.7
 Diet+PA 120.6±18.6 0.300 109.3±16.2 −11.0±7.3 <.0001 −11.1 −12.9 −9.2 0.016 −11.0765 −12.92 −9.235 0.013
 Diet 117.4±16.4 109.0±16.1 −8.1±6.0 <.0001 −8.1 −9.7 −6.6 −8.0393 −9.581 −6.498
BMI, kg/m2
 Lean control 21.9±1.1
 Diet+PA 43.5±4.82 0.848 39.6±4.6 −3.9±2.5 <.0001 −3.9 −4.5 −3.3 0.050 −3.9 −4.6 −3.3 0.044
 Diet 43.68±5.93 40.6±5.6 −3.1±2.3 <.0001 −3.1 −3.7 −2.5 −3.1 −3.7 −2.5
FPG, mg/dL
 Lean control 91±6
 Diet+PA 94±12 0.798 90±10 −3±10 0.014 −3 −6.0 −0.9 0.637 −3.1 −5.7 −0.6 0.674
 Diet 93±11 91±11 −3±10 0.044 −3 −5.3 0.2 −2.3 −5.1 0.4
Fins, mU/L
 Lean control 3.6±1.7
 Diet+PA 17.1±9.2 0.445 11.7±6.0 −5.3±8.2 <.0001 −5.3 −7.3 −3.4 0.359 −5.1 −7.1 −3.1 0.470
 Diet 15.8±9.5 11.9±6.5 −4.0±9.1 0.003 −3.9 −6.4 −1.5 −3.9 −6.3 −1.5
HOMA-IR
 Lean control 0.80±0.38
 Diet+PA 4.03±2.45 0.367 2.62±1.4 −1.40±2.20 <.0001 −1.41 −1.94 −0.88 0.203 −1.33 −1.86 −0.80 0.275
 Diet 3.66±2.19 2.77±1.63 −0.95±2.16 0.003 −0.9 −1.47 −0.34 −0.88 −1.44 −0.32
HOMA-B, %
 Lean control 48±26
 Diet+PA 217±123 0.896 184±138 −32±132 0.072 −32 −65.0 1.0 0.576 −31.1 −64.4 2.1 0.519
 Diet 213±175 162±109 −44±135 0.036 −47 −85.5 −9.0 −47.5 −84.1 −10.8
QUICKI
 Lean control 0.41±0.05
 Diet+PA 0.32±0.03 0.261 0.34±0.03 0.02±0.03 <.0001 0.02 0.01 0.03 0.371 0.02 0.01 0.02 0.448
 Diet 0.33±0.03 0.34±0.03 0.02±0.03 <.0001 0.01 0.01 0.02 0.01 0.01 0.02
WC, cm
 Lean control 76.6±6.8
 Diet+PA 124.4±12.5 0.215 116.2±10.6 −8.3±6.5 <.0001 −8.2 −9.8 −6.6 0.004 −8.2 −9.8 −6.5 0.004
 Diet 121.7±11.8 116.0±10.8 −5.0±5.4 <.0001 −5.1 −6.5 −3.7 −5.0 −6.4 −3.6
SBP, mmHg
 Lean control 109±13
 Diet+PA 135±14 0.680 132±14 −4±15 0.066 −3.7 −7.5 0.0 0.052 −3.6 −7.4 0.2 0.520
 Diet 134±14 133±16 −2±16 0.349 −1.8 −5.9 2.2 −1.8 −5.9 2.3
HDL-C, mg/dL
 Lean control 56±13 −1±12
 Diet+PA 47±10 0.451 44±10 −1±12 0.028 −2.4 −4.3 −0.5 0.294 −2.2 −4.1 −0.4 0.280
 Diet 491±12 45±12 −1±12 <.0001 −3.7 −5.3 −2.0 −3.6 −5.3 −1.9
TG, mg/dL
 Lean control 66±32
 Diet+PA 128±68 0.772 124±56 −6±57 0.440 −4.8 −18.9 9.2 0.111 −4.5 −18.7 9.6 0.076
 Diet 124±57 133±55 9±39 0.068 9.3 −0.9 19.6 11.0 1.3 20.8
IL-6, pg/mL
 Lean control 0.80±1.39
 Diet+PA 2.81±1.57 0.661 5.4±5.78 2.6±5.8 0.001 2.59 1.1 4.1 0.816 2.7 1.2 4.2 0.806
 Diet 2.67±2.03 5±7.38 2.14±7.1 0.022 2.32 0.5 4.2 2.4 0.6 4.3
hs-CRP, mg/L
 Lean control 1.7±3.2
 Diet+PA 9.3±8.0 0.289 3.8±4.2 −5±6.7 <.0001 −5.3 −7.0 −3.6 0.355 −5.1 −6.8 −3.4 0.427
 Diet 7.8±7.7 3.8±4.2 −4.5±6.9 <.0001 −4.2 −5.8 −2.5 −4.1 −5.8 −2.4
Leptin, ng/mL
 Lean control 6.9±4.5
 Diet+PA 51.7±21.93 0.308 39.1±20.4 −13.8±22.6 <.0001 −12.2 −16.6 −7.8 0.659 −12.5 −17.0 −8.1 0.628
 Diet 55.9±24.9 41.1±20.0 −13.7±20.5 <.0001 −13.8 −19.2 −8.5 −14.2 −19.5 −8.8
Adiponectin, pg/mL
 Lean control 10654±8217
 Diet+PA 6357±4527 0.877 5827±3061 −747±3254 0.102 −658 −1477 161 0.299 −721 −1557 114 0.290
 Diet 6481±4331 6405±3073 82±3580 0.897 −2 −928 924 −55 −984 873
Fat mass, kg
 Diet+PA 60±12 0.582 52±11 −9±6 <.0001 −8.6 −10.2 −7.0 0.007 −8.7 −10.3 −7.1 0.007
 Diet 59±11 53±12 −6±5 <.0001 −5.9 −7.1 −4.7 −5.9 −7.1 −4.7
Fat free mass, kg
 Diet+PA 59±10 0.197 56±9 −2±3 <.0001 −2.4 −3.1 −1.8 0.448 −2.4 −3.1 −1.7 0.324
 Diet 57±8 54±8 −2±3 <.0001 −2 −2.8 −1.3 −1.9 −2.6 −1.2
L/S ratio
 Diet+PA 1.05±0.24 0.419 1.19±0.18 0.13±0.18 <.0001 0.13 0.08 0.17 0.019 0.13 0.08 0.17 0.015
 Diet 1.09±0.24 1.14±0.16 0.06±0.15 0.006 0.06 0.02 0.10 0.05 0.02 0.09
ABDSUB, cm2
 Diet+PA 717±163 0.962 607±150 −115±105 <.0001 −114 −140 −88 0.171 −74 −165 17 0.160
 Diet 718±192 632±168 −91±90 <.0001 −90 −113 −66 −90 −114 −66
ABDVIS, cm2
 Diet+PA 196±84 0.470 171±66 −29±61 0.001 −27 −43 −12 0.647 −29 −44 −14 0.555
 Diet 186±69 163±51 −22±48 0.002 −23 −36 −10 −23 −35 −10
Daily step counts, steps
 Diet+PA 7239±3168 0.827 8692±3051 1369±2789 0.001 1399 681 2117 0.030 1409 696 2122 0.030
 Diet 7124±2604 7583±2964 404±1859 0.127 413 −90 915 413 −88 914
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a

Between Diet+PA and Diet

b

Before and after weight loss

c

Using mixed model repeated measures

ANGPTL8: Angiopoietin-like protein 8; PA: physical activity; BMI: body mass index; FPG: fasting plasma glucose; Fins: fasting insulin; HOMA-IR: Homeostatic model assessment-insulin resistance; HOMA-B: Homeostatic model assessment-insulin resistance-b cell function; QUICKI: quantitative insulin-sensitivity check index; WC: waist circumference; SBP: systolic blood pressure; HDL-C: high-density lipoprotein-cholesterol; TG: triglycerides; IL-6: interleukin 6; hs-CRP: high sensitivity c-reactive protein; L/S ratio: liver-to-spleen ratio; ABDSUB: abdominal subcutaneous adipose tissue; ABDVIS: abdominal visceral adipose tissue.

4. Discussion

There are two novel findings in our current study. First, in a cohort of northern Americans with obesity but without diabetes, circulating total ANGPTL8 was associated with obesity at baseline and decreased after weight loss intervention; however, the reduction in ANGPTL8 after weight loss intervention did not significantly differ between the intervention groups, even though weight reduction was significantly greater in the diet plus physical activity group. Second, physical activity had an additive effect with diet in promoting weight loss, in association with improvement in fat mass, liver-to-spleen ratio, but not abdominal adipose tissue, even with only a relatively small increase in physical activity (~987 steps per day).

Circulating ANGPTL8 has emerged as a potential therapeutic target due to its mechanistic link to metabolic phenotypes and increased circulating levels in individuals with obesity or type 2 diabetes mellitus (T2DM) [33, 43, 44]. Current evidence suggests that ANGPTL8 is secreted by liver and adipose tissue and binds to other ANGPTL8 proteins (i.e. ANGTPL3 and ANGPTL4) to regulate LPL activity and, subsequently, triacylglycerol partitioning towards storage or oxidation [45]. For example, serum ANGPTL8 increases in response to feeding to promote adipose tissue lipid storage. However, very little is known about ANGPLT8 in humans in the context of potential medically-relevant conditions (i.e. obesity, diabetes) or their treatment (i.e. chronic hypocaloric diet, physical activity, weight loss). We hypothesized that serum ANGTPL8 would be higher in obesity and decreased by weight loss intervention with diet and diet plus physical activity, and that, physical activity would have an additive effect. Our results confirm our hypothesis with the exception that physical activity did not further reduce serum ANGPTL8 beyond diet alone, even though it did further improve weight loss.

Our findings are consistent with data from Hu et al that demonstrate decreased in serum full-length (rather than total) ANGPTL8 following weight loss intervention [32]. However, there are several notable differences between these two studies. First, the characteristics of the two study populations are quite different. Our study population consisted of northern Americans with severe obesity (BMI greater than or equal to 35 kg/m2) and insulin resistance but without overt T2DM. In contrast, their study population consisted of leaner Chinese subjects (average BMI of 29.1 kg/m2) with newly diagnosed T2DM. Thus, the main conclusions, that ANGPTL8 is greater with obesity and decreases with weight loss intervention is further strengthened by the similar findings in these two divergent populations. Second, though both studies performed a 6-month weight loss intervention consisting of diet alone or diet plus physical activity, their study did not achieve significant differences in weight loss between these two groups, and therefore could not assess the additive effect of physical activity on serum ANGPTL8. In our study, the addition of physical activity to diet did produce significantly greater loss of weight as well as fat mass and liver fat, perhaps because our study subjects had more severe obesity at baseline and lost more weight overall. Despite this greater weight loss, serum ANGPTL8 was not different between diet versus diet plus physical activity after the 6-month intervention. It is possible that our study did not achieve a great enough difference in weight loss between the two intervention groups to achieve a detectable difference in serum ANGPTL8. This possibility is supported by the observation that other serum factors likewise did not differ between interventions groups, even though these serum factors had robust pre- to post-intervention changes.

Another possibility is that there may be a floor effect, i.e. that serum ANGPTL8 decreases asymptomatically towards a physiologic minimum, beyond which counterregulatory responses resist further change (as is observed with other aspects of weight loss). In addition, there may be organ-specific or fat depot-specific differences in ANGPTL8 secretion and/or catabolism. This possibility is supported by the observation that physical activity plus diet compared to diet alone results in greater loss of weight, fat mass (total), and liver fat but not abdominal subcutaneous or visceral fat mass. Finally, serum ANGPTL8 levels may be influenced by numerous, as yet unknown, systemic as well as local factors associated with energy balance, i.e. adrenergic activity. Overall, these data suggest that serum ANGPTL8 is influenced by weight and/or adiposity-dependent as well as –independent mechanisms, and that physical activity is not sufficient for further reduce serum total ANGPTL8 beyond diet alone.

Another difference between our study and Hu et al. is that, we measured serum total ANGPTL8 whereas they measured only full-length ANGPTL8. Issues related to measuring total (which includes C-terminal plus full-length) versus full-length ANGPTL8 has been previously reported [41]. The two most commonly used ELISA kits measure either human full-length ANGPTL8 (EIAAB) or total ANGPTL8 (Phoenix kits). Additional commercial ELISA kits that detect ANGPTL8 have emerged more recently [33, 46–49]. The role of ANGPTL8 should be studied and compared with the same ELISA kits in order to more clearly understand the relationship between ANGPTL8 and relevant phenotypes in humans. There are few studies measuring full-length ANGPTL8 and total ANGPTL8 in the same biospecimens. Abu-Farha et al measured both full-length ANGPTL8 (EIAAB) and total ANGPTL8 (Phoenix) in Asian subjects with obesity who underwent an exercise training intervention. This study found that full-length ANGPTL8 was increased in obesity (P=0.002), and total ANGPTL8 had an increased trend in obesity (P=0.058) [37]. Furthermore, in their study, full-length ANGPTL8 was decreased and total ANGPTL8 tended to be decreased (P=0.015 and P=0.058, respectively) following a 3-month exercise intervention, even though the degree of weight loss did not differ after the intervention [37]. Thus, this study suggests that exercise alone may also influence serum total and full-length ANGPTL8 independent of weight loss.

The main published studies examining ANGPTL8 in response to diet and/or physical activity interventions are summarized as follows: 1) in Abu Farha et al., exercise training with a combination of both moderate-intensity of aerobic and resistance training for a 3-month period resulted in a decrease of full-length ANGPTL8 and a decreased trend of total ANGPTL8 without significant weight loss in Asians with obesity [37]; 2) in Hu et al., a 6-month lifestyle intervention with diet or diet plus physical activity decreased full-length ANGPTL8 with no difference in weight loss or full-length ANGPTL8 between the two intervention groups in Asians with obesity and diabetes [32]; and 3) in our study, a 6-month lifestyle intervention with diet or diet plus physical activity decreased total ANGPTL8 with no difference in serum total ANGPTL8 between the two intervention groups despite greater loss of weight, fat mass, and liver fat in northern Americans with obesity but without diabetes. Together these data suggest that diet-mediated weight loss, physical activity without weight loss, but not physical activity added to diet-mediated weight loss are sufficient to reduce serum ANGPTL8.

In addition to the relationship between serum total ANGPTL8 and obesity and weight loss, ANGPTL8 was associated with liver-spleen ratio, an established surrogate marker of non-alcoholic fatty liver disease (NAFLD). In line with our results, hepatic expression of ANGPTL8 was positively associated with different stages of NAFLD in rodents and humans with obesity [16, 50, 51]. Despite this relationship between ANGPTL8 and NAFLD, serum ANGPTL8 was not associated with fat mass, abdominal visceral adipose tissue or abdominal subcutaneous adipose tissue. Furthermore, improvement in the L/S ratio was associated with a reduction in serum total ANGPTL8 in both diet only and diet plus physical activity interventions. L/S ratio improved more significantly in diet plus physical activity group than in the diet only group. However, serum ANGPTL8 did not decreased significantly more in diet plus physical activity group than in diet only group. Previous studies have reported a positive relationship between serum ANGPTL8 and NAFLD [48, 50]. However, another study showed that serum ANGPTL8 was similar in the subjects with and without NAFLD, and it also demonstrated that there was no correlation between serum ANGPTL8 and the degree of hepatosteatosis [49]. This finding is possibly due to differences in the ELISA kit used and the complicated proteolytic regulation of ANGPTL8 in vivo [41, 49]. Our findings are consistent with Lee YH et al’s result with the same ELISA kits in which circulating total ANGPTL8 was associated with NAFLD. Physical activity had additive effect to diet alone in improving NAFLD and it may be due to greater weight loss in the diet plus physical activity compared to the diet only group. Serum total ANGPTL8 levels were decreased in association with improvement in L/S ratio. This finding suggests that total serum ANGPTL8 may be influenced by hepatic steatosis.

Our study has some limitations. First, we did not assess an exact causal relationship between serum total ANGPTL8 and weight loss, although this is a prospective study. Second, we did not collect information on dietary protein sources and, therefore, could not assess its effects on relevant outcomes. Such information might be relevant given a previous study demonstrating that animal-derived protein intake may decrease serum total ANGPTL8[35]. On a related note, our study collected blood in the morning after an overnight fast, when serum ANGPTL8 levels are relatively low. Third, our study only enrolled predominantly female, northern American subjects and may not be generalizable to other races/populations.

5. Conclusion

In conclusion, among northern Americans with obesity but without diabetes, ANGPTL8 was significantly associated with obesity, and was significantly decreased following a 6- month weight loss intervention (diet only or diet plus physical activity). The addition of physical activity produced greater weight loss as well as improvement in associated some metabolic parameters (i.e. BMI, WC, fat mass and liver-spleen ratio), but not others (i.e. abdominal adipose tissue). The addition of physical activity to diet did not promote further significant decline of serum total ANGPTL8 compared to diet alone. These data add to the growing body of evidence implicating ANGPTL8 in human health and disease.

Highlights.

  • Physical activity had an additive effect with diet in promoting loss of weight.

  • Circulating total ANGPTL8 was positively associated with obesity at baseline.

  • Circulating total ANGPTL8 was decreased after weight loss intervention.

  • The reduction in ANGPTL8 did not significantly differ in both intervention groups.

Acknowledgments

This work was supported by grants from National Institutes of Health (NIH) T32 DK007052 (HA and VLR)

Footnotes

Disclaimers:

All authors disclose no conflict of interest.

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