An alternative approach in determining cause, treatment, and prevention of obesity is to study those who appear resistant to the obesogenic environment. We examined appetite responses in 33 obesity resistant individuals (ORI) versus 28 obesity susceptible individuals (OSI). Fingerprick blood samples to measure ghrelin, total peptide YY (PYY), leptin, glucose, and insulin along with appetite ratings were collected at baseline and 15, 30, 60, 120, and 180 min following consumption of a standardized meal. Fasting, area under the curve (AUC), peak/nadir, and time to peak/nadir were compared. Participants completed the three factor eating questionnaire (TFEQ). No significant differences were observed for ghrelin or PYY. Higher leptin concentrations in the OSI disappeared after controlling for percent body fat (%BF). Significant differences in appetite ratings included a lower hunger nadir among OSI compared with ORI (
Obesity is well-recognised as a disease process leading to multiple pathological consequences. The WHO declared obesity to be an epidemic in 1998 [
Some obesity experts have made dire predictions for future obesity prevalence rates. For instance, Wang et al. [
Most obesity researchers have investigated the characteristics of overweight and obese individuals and populations in an attempt to determine the cause, treatment, and prevention of obesity. An alternative approach is to study those who have remained lean despite living in an obesogenic environment. Information from this group may allow us to develop novel strategies to benefit those who continually struggle to maintain a healthy body weight.
One potential difference between those who struggle with their weight and those who remain lean with seeming ease may involve appetite regulation. Several hormones have important roles in regulating appetite. For example, ghrelin, an orexigenic peptide, appears important in meal initiation [
Some [
It would therefore be of interest to compare the hormone profiles of those who report they remain lean with relative ease (ORI) with those who report they struggle to maintain a healthy body weight (OSI). As some studies have shown that ghrelin secretion mirrors reported hunger [
We investigated hormone concentrations and appetite indices in response to a standard meal among those who remain lean with ease and those who constantly struggle with their weight.
Sixty-one participants were recruited from the general public in Dunedin, New Zealand, via the distribution of flyers, designed with specific questions to target obesity susceptible and obesity resistant individuals, around local supermarkets, advertising in the local newspaper, and emails sent to University staff.
To be eligible, participants were required to be healthy males or females aged between 20 and 45 years. Participants completed a screening questionnaire to see if they met our study criteria as either an obesity susceptible individual (OSI) (struggles to maintain their weight, despite perceived low energy intakes) or an obesity resistant individual (ORI) (remains lean with relative ease and can eat whatever they like). Participants were classified as OSI if they answered positively to either or both of the following two statements:
Conversely, participants were classified as ORI if they answered positively to any of the following statements:
Participants were excluded if they did not answer positively to any of the screening tool questions, had a thyroid disorder, or were menopausal. In total 28 OSI and 33 ORI were recruited. Obesity resistant individuals had a BMI of 17.5–27.7 kg/m2, had always been lean (as indicated by self-reported weight history), and found it difficult to gain but not lose weight. In contrast, OSI had a BMI of 21.6–44.0 kg/m2, were likely to experience fluctuations in weight (as indicated by self-reported weight history), and found it difficult to lose but not gain weight. The study protocol was approved by the Human Ethics Committee of the University of Otago, New Zealand. All participants provided written informed consent.
Each participant attended a 4 h clinic visit at the Department of Human Nutrition, University of Otago. Participants arrived at the clinic after an overnight fast of at least 10 h. A fasting fingerprick blood sample using a disposable lancet was taken for measurement of ghrelin (active), PYY (total), leptin, glucose, and insulin. Capillary blood samples were collected in microcentrifuge tubes containing potassium EDTA. This was followed by the consumption of a standardised meal that participants were asked to consume within 15 min. Further capillary blood samples were collected at 15, 30, 60, 120, and 180 min following the start of ingestion of the meal. Participants also completed an appetite questionnaire at each blood sampling time-point.
The standardized meal was designed to provide 2440 kJ (584 kcal) for females and 2928 kJ (700 kcal) for males made up of 55, 29, and 15 percent of the total energy intake from carbohydrate, fat, and protein, respectively.The meal was comprised of a muesli cereal (containing oats, wheat germ, Special K (Kelloggs), brown sugar, desiccated coconut, skimmed milk powder, full fat milk, canola oil, almonds, sultanas, dried apricots, sunflower seeds), milk, yoghurt, and orange juice. Participants were required to consume the entire standardized meal. Because the response of important study variables (namely, ghrelin, PYY, and appetite scores) has been shown to be proportional to caloric intake and because this study was cross-sectional, we decided to fix caloric intake for each sex to reduce interindividual variability.
Capillary blood samples (1 mL) were collected in 1.5 mL microcentrifuge tubes containing 10
Ghrelin (active), PYY (total), leptin, and insulin were analysed using immunoassay (Human Gut Hormone Panel LINCOplex Kit, LINCO Research, St. Charles, MO, USA). The minimum detectable concentrations for the hormones were 1.8 pg·mL−1 for ghrelin (active), 8.4 pg·mL−1 for PYY (total), 157.2 pg·mL−1 for leptin, and 44.5 pg·mL−1 for insulin. The coefficient of variation for measurements of ghrelin, PYY (total), leptin, and insulin was 13.0%, 8.1%, 11.8%, and 8.4% respectively.
Area under the curve (AUC) for ghrelin, PYY (total), leptin, glucose, and insulin was calculated by the trapezoid method.
At each blood sampling time-point participants completed a series of appetite related questions using a 10 cm visual analogue scale (VAS) [
Body weight was measured on calibrated electronic scales (Wedderburn) that measured to the nearest 0.01 kg. Height was measured to the nearest millimeter using a stadiometer. Body composition including lean mass, fat mass, and body fat percentage (%BF) was measured using dual-energy X-ray absorptiometry (DXA) (manufacturer info DPX-L Scanner, Lunar Corp., Cincinnati, OH, USA) using software version 1.35 (Lunar, Cincinnati, OH, USA) at the Dunedin Public Hospital Dual X-Ray Absorptiometry Scanning Unit. Following screening, participants also completed a questionnaire regarding past-weight history. Weight history information was not used to further categorise the participants, but it did confirm their status as obesity resistant or obesity susceptible. When entering the study participants self-reported being weight stable.
The primary outcome measure to be assessed was the postprandial change in ghrelin. Thirty participants per group (OSI and ORI) were required to detect a difference of 5% in the serial measurements of ghrelin with a power of 90% and alpha 0.05. Participant characteristics are presented as arithmetic means and standard deviations (SD). The results show the differences for sex adjusted for obesity resistance/susceptibility category (ORS) and differences for ORS adjusted for sex from regression analysis. A further adjustment %BF was conducted by including a term for %BF in the regression model. An interaction between sex and ORS group was considered but as it was not statistically significant it was not included in the final model. The fasting and AUC hormone variables were log transformed before analysis. The results are presented as medians (interquartile range). No adjustment was made for multiple testing. Statistical analysis was performed using STATA Version 12 (STATA Inc., College Station, TX).
The characteristics of study participants are shown in Table
Characteristics of obesity resistant individuals (ORI) and obesity susceptible individuals (OSI).
ORI | OSI |
| |||
---|---|---|---|---|---|
Females | Males | Females | Males | ||
|
16 | 17 | 15 | 13 | |
Age (years) | 32.6 (7.6) | 30.6 (7.7) | 35.0 (7.7) | 35.5 (9.1) | 0.081 |
Weight (kg) | 56.3 (5.3) | 73.3 (10.7) | 86.6 (15.2) | 94.1 (11.0) | <0.001 |
Height (m) | 1.65 (0.06) | 1.81 (0.08) | 1.66 (0.05) | 1.79 (0.04) | 0.400 |
WC (cm) | 71.6 (6.0) | 80.4 (4.7) | 95.6 (10.8) | 99.4 (11.7) | <0.001 |
BMI (kg/m2) | 20.6 (1.8) | 22.3 (2.9) | 31.6 (6.2) | 29.5 (3.3) | <0.001 |
LBM (kg) | 40.1 (4.2) | 58.5 (9.1) | 45.8 (3.7) | 63.7 (7.6) | 0.002 |
Fat Mass (kg) | 13.1 (2.9) | 11.3 (4.6) | 37.2 (14.2) | 26.1 (8.1) | <0.001 |
% Body Fat | 23.4 (4.8) | 15.4 (5.6) | 41.9 (9.9) | 27.6 (7.1) | <0.001 |
TSH ( |
1.45 (0.96) | 1.78 (0.97) | 1.67 (0.77) | 1.58 (0.82) | 0.958 |
All values are means (standard deviation).
BMI: Body Mass Index, LBM: Lean Body Mass, TSH: Thyroid Stimulating Hormone (reference range = 0.3–5
Fasting, AUC, peak or nadir, and time to peak or nadir results for ghrelin, PYY (total), leptin, glucose, and insulin adjusted for ORS and sex with and without adjustment for %BF are presented in Table
Hormone profiles in obesity resistant individuals (ORI) and obesity susceptible individuals (OSI) in response to a standardised meal.
ORI | OSI |
|
|
|
|||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Females | Males | Females | Males | ||||||||||||
|
Median | Interquartile Range |
|
Median | Interquartile Range |
|
Median | Interquartile Range |
|
Median | Interquartile Range | ||||
Ghrelin | |||||||||||||||
Fasting (pg·mL−1) | 14 | 70.7 | 39.2–129.5 | 17 | 55.2 | 38.6–137.3 | 12 | 69.3 | 59.5–105.5 | 12 | 55.0 | 35.6–65.1 | 0.319 | 0.600 | 0.662 |
AUC (mmol·min−1) | 11 | 12596 | 7470–16987 | 16 | 11341 | 8747–21848 | 9 | 11232 | 9252–14968 | 9 | 9889 | 6136–10693 | 0.857 | 0.460 | 0.751 |
Nadir (pg·mL−1) | 16 | 44.9 | 31.5–55.3 | 17 | 33.7 | 27.1–56.7 | 14 | 39.4 | 31.2–46.7 | 13 | 35.3 | 18.0–38.7 | 0.419 | 0.287 | 0.822 |
Time to nadir (min) | 16 | 60 | 30–60 | 17 | 60 | 60-60 | 14 | 30 | 30–60 | 13 | 60 | 60-60 | 0.058 | 0.518 | 0.580 |
PYY | |||||||||||||||
Fasting (pg·mL−1) | 14 | 47.9 | 40.1–53.7 | 17 | 55 | 47.8–65.3 | 14 | 47.1 | 37.5–67.3 | 12 | 56.4 | 49.4–62.0 | 0.161 | 0.889 | 0.761 |
AUC (mmol·min−1) | 13 | 11700 | 10954–13230 | 16 | 12511 | 10524–13597 | 12 | 12779 | 10777–18752 | 9 | 12877 | 12436–13739 | 0.825 | 0.601 | 0.736 |
Peak (pg·mL−1) | 16 | 72.6 | 68.2–82.0 | 17 | 77.8 | 66.7–87.5 | 15 | 75.4 | 55.0–112.4 | 13 | 75.7 | 68.7–87.5 | 0.981 | 0.877 | 0.916 |
Time to peak (min) | 16 | 60 | 45–120 | 17 | 60 | 30–120 | 15 | 120 | 60–180 | 13 | 30 | 30-30 | 0.275 | 0.584 | 0.526 |
Leptin | |||||||||||||||
Fasting (pg·mL−1) | 16 | 2426 | 1367–3626 | 17 | 693.4 | 440.9–1495.0 | 15 | 14367 | 4135–24941 | 12 | 2480 | 1424–8725 |
|
|
0.324 |
AUC (mmol·min−1) | 16 | 425506 | 231672–582562 | 16 | 101878 | 74897–237294 | 14 | 1753714 | 502753–4671533 | 9 | 410572 | 268776–1746261 |
|
|
0.378 |
Nadir (pg·mL−1) | 16 | 2003 | 1184–2986 | 17 | 531.7 | 339.7–1313.4 | 15 | 9015 | 2661–24450 | 13 | 2108 | 1198–6836 |
|
|
0.946 |
Time to nadir (min) | 16 | 60 | 15–120 | 17 | 60 | 30–120 | 15 | 60 | 15–120 | 13 | 60 | 30–120 | 0.781 | 0.558 | 0.949 |
Glucose | |||||||||||||||
Fasting (mmol·L−1) | 16 | 5.30 | 5.00–5.53 | 17 | 5.25 | 4.95–5.40 | 15 | 5.25 | 5.05–5.30 | 13 | 5.25 | 5.05–5.50 | 0.851 | 0.900 | 0.887 |
AUC (mmol·min−1) | 16 | 1030 | 995–1063 | 17 | 1054 | 1013–1081 | 15 | 1062 | 970–1128 | 13 | 1048.0 | 992–1113 | 0.298 | 0.252 | 0.954 |
Peak (mmol·L−1) | 16 | 6.9 | 6.70–7.55 | 17 | 7.3 | 7.00–8.00 | 15 | 7.2 | 6.7–7.8 | 13 | 7.5 | 7.10–7.60 |
|
0.540 | 0.759 |
Time to peak (min) | 16 | 15 | 15–30 | 17 | 30 | 30-30 | 15 | 30 | 15–30 | 13 | 30 | 30-30 | 0.103 | 0.072 | 0.352 |
Insulin | |||||||||||||||
Fasting (pg·mL−1) | 13 | 157 | 131.1–177.1 | 15 | 236.7 | 110.3–299.6 | 14 | 252.2 | 187.0–355.5 | 11 | 398 | 281.3–466.5 | 0.085 |
|
0.213 |
AUC (mmol·min−1) | 12 | 105038 | 92640–143522 | 14 | 139943 | 108035–171234 | 12 | 175434 | 104685–217197 | 8 | 213250 | 131498–321104 | 0.057 |
|
0.802 |
Peak (pg·mL−1) | 16 | 1345.1 | 965.9–1867.8 | 17 | 1677.5 | 1250.4–2298.3 | 15 | 1467.9 | 1098.9–2294.6 | 13 | 1849 | 1453–2475 | 0.145 | 0.196 | 0.632 |
Time to peak (min) | 16 | 30 | 30-30 | 17 | 30 | 30-30 | 15 | 30 | 30-30 | 13 | 30 | 30-30 | 0.466 | 0.379 | 0.716 |
%BF: percent body fat, AUC: area under the curve, ORS: obesity resistance/susceptibility category.
Fasting and AUC data have been log transformed, *
No differences related to ORS or sex were observed in the analysis of ghrelin or PYY.
Fasting leptin concentration and leptin AUC were significantly greater in females compared to males. The nadir for leptin was also higher in females compared with males. However, these differences disappeared when controlling for %BF. Fasting leptin concentration, leptin AUC, and nadir for leptin were all lower in ORI compared with OSI. Again, these differences disappeared when controlling for %BF. No differences were observed in the leptin time to nadir.
There were no significant differences for fasting, AUC, or time to peak for blood glucose for OSI versus ORI or males versus females. Peak blood glucose was significantly higher in males compared to females. Fasting insulin and insulin AUC were significantly lower in ORI compared with OSI. These differences disappeared when controlling for %BF.
Fasting, AUC, peak or nadir, and time to peak or nadir results for “hunger,” “desire to eat,” “fullness,” and “preoccupation with thoughts of food” adjusted for ORS and sex with and without adjustment for %BF are presented in Table
Appetite ratings for obesity resistant individuals (ORI) and obesity susceptible individuals (OSI) in response to a standardised meal.
ORI | OSI |
|
|
|
|||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Females | Males | Females | Males | ||||||||||||
|
Median | Interquartile Range |
|
Median | Interquartile Range |
|
Median | Interquartile Range |
|
Median | Interquartile Range | ||||
Hunger | |||||||||||||||
Fasting (mm) | 16 | 73 | 55–86 | 17 | 67 | 49–84 | 15 | 65 | 51−77 | 13 | 60 | 40−70 | 0.515 | 0.074 | 0.341 |
AUC (mm·min−1) | 16 | 9049 | 4819–10084 | 17 | 6413 | 4200–10358 | 15 | 4275 | 2798−6780 | 13 | 6158 | 5528−9443 | 0.506 | 0.056 | 0.785 |
Nadir (mm) | 16 | 22 | 2–30 | 17 | 19 | 10–36 | 15 | 1 | 0−4 | 13 | 9 | 1−27 | 0.170 |
|
0.414 |
Time to Nadir (min) | 16 | 15 | 15–30 | 17 | 30 | 15–60 | 15 | 15 | 15−30 | 13 | 15 | 15−30 | 0.656 | 0.305 | 0.252 |
Fullness | |||||||||||||||
Fasting (mm) | 15 | 13 | 5–20 | 17 | 16 | 6–28 | 15 | 14 | 3-41 | 13 | 17 | 1−28 | 0.871 | 0.918 | 0.826 |
AUC (mm·min−1) | 15 | 7095 | 6158–8670 | 17 | 6720 | 4800–10125 | 15 | 10185 | 6600−11295 | 13 | 7088 | 5595−7598 | 0.053 | 0.451 | 0.470 |
Peak (mm) | 16 | 76 | 64–95 | 17 | 71 | 49–77 | 15 | 90 | 74−96 | 13 | 63 | 51−77 | 0.817 | 0.482 | 0.754 |
Time to peak (min) | 16 | 15 | 15–30 | 17 | 15 | 15–30 | 15 | 15 | 15−30 | 13 | 30 | 15−30 | 0.380 | 0.119 | 0.860 |
Preoccupation with Food | |||||||||||||||
Fasting (mm) | 16 | 63 | 49–85 | 17 | 34 | 28–63 | 15 | 57 | 30−70 | 13 | 41 | 15−68 |
|
0.448 | 0.987 |
AUC (mm·min−1) | 16 | 6008 | 3173–8948 | 17 | 4628 | 2805–10830 | 15 | 2813 | 1875−7155 | 13 | 6660 | 2378−8663 | 0.496 | 0.294 | 0.455 |
Nadir (mm) | 16 | 15 | 4–31 | 17 | 10 | 4–27 | 15 | 1 | 0−8 | 13 | 15 | 1−25 | 0.309 | 0.193 | 0.871 |
Time to Nadir (min) | 15 | 15 | 15–30 | 17 | 30 | 15–30 | 15 | 15 | 15−30 | 13 | 15 | 15−60 | 0.092 |
|
0.888 |
Desire to Eat | |||||||||||||||
Fasting (mm) | 16 | 76 | 58–85 | 17 | 64 | 45–85 | 15 | 69 | 49−79 | 13 | 61 | 35−72 | 0.336 | 0.199 | 0.243 |
AUC (mm·min−1) | 16 | 8456 | 4943–10609 | 17 | 6473 | 4118–10913 | 15 | 3900 | 2753−6938 | 13 | 6705 | 5723−9788 | 0.389 | 0.148 | 0.427 |
Nadir (mm) | 16 | 25 | 2–31 | 17 | 18 | 10–31 | 15 | 2 | 0−5 | 13 | 15 | 1−31 | 0.134 | 0.059 | 0.745 |
Time to Nadir (min) | 16 | 15 | 15–30 | 17 | 15 | 15–30 | 15 | 15 | 15−30 | 13 | 30 | 15−60 | 0.770 | 0.923 | 0.940 |
TFEQ | |||||||||||||||
Dietary Restraint | 16 | 4 | 0–12 | 17 | 4 | 3–5 | 15 | 9 | 3−18 | 13 | 6 | 4−8 | 0.337 |
|
|
Disinhibition | 16 | 3 | 1–10 | 17 | 3 | 2–5 | 15 | 12 | 3−15 | 13 | 7 | 5−10 | 0.255 |
|
|
Hunger | 16 | 8 | 1–13 | 17 | 8 | 3–9 | 15 | 6 | 1−13 | 13 | 8 | 4−10 | 0.791 | 0.749 | 0.665 |
%BF: percent body fat, AUC: area under the curve, ORS: obesity resistance/susceptibility category, TFEQ: three factor eating questionnaire.
The nadir for “hunger” was significantly lower for OSI compared with ORI. The fasting rating of “preoccupation with thoughts of food” was significantly higher in females compared with males. Differences were also observed in the time to nadir for the “preoccupation with thoughts of food” rating, with the nadir occurring significantly later in ORI versus OSI. These differences disappeared after controlling for %BF. There were no significant differences observed in fasting, AUC, peak, or time to peak for ratings of “fullness” or “desire to eat.”
The TFEQ results are presented in Table
Three-factor eating questionnaire (TFEQ) scores for obesity resistant (OR) females (F) and males (M) versus obesity susceptible (OS) females (F) and males (M). Values are medians in 25th and 75th interquartile range. *= obesity resistant < obesity susceptible
Why some individuals remain lean with relative ease while others constantly struggle with their body weight, despite living in a similar environment, is an intriguing question. Although the majority of research in the obesity field has focused on the characteristics of obese individuals, an alternative approach is to compare the characteristics of those who are seemingly resistant to obesity (ORI) with those who appear highly susceptible (OSI). One reason for the difference in weight gain susceptibility may be due to physiological differences in appetite control. We studied the hormonal response to a standardized meal amongst ORI and OSI. Despite some differences in absolute values of these hormones, the patterns of change in response to a standard meal were remarkably similar between ORI and OSI.
As expected, ghrelin concentrations decreased in all groups upon feeding reaching a nadir between 30 and 60 min. Ghrelin, an orexigenic hormone, is acutely negatively regulated by the ingestion of meals and positively regulated by fluxes in overall energy balance [
Similar gherlin concentrations, despite different body composition and therefore energy stores, have also been observed in the study cohorts of two previous studies. Khoury et al. [
The similarities in ghrelin concentration among the two groups may reflect two different mechanisms. Whereas the OSI ghrelin levels are due to increased energy stores, the ORI may have lower than predicted ghrelin levels due to a possible underlying protective mechanism which theoretically could protect against overeating and subsequent weight gain. Thus, no obvious difference between the two groups is apparent. Obesity resistance individuals may differ from other populations previously studied in that they largely struggle to gain weight rather than simply being lean. One previous study that investigated constitutionally thin (i.e., those who find it difficult to gain weight) also found lower ghrelin levels than expected given their low %BF [
PYY is an anorexigenic hormone that has been associated with meal satiety and thus theoretically meal termination [
Consistent with results from previous studies where higher leptin concentrations have been associated with increases in BMI [
In the face of similar hormone patterns it would have been of interest to observe how much our two groups would have eaten when presented with an
In addition to the potential differential response to the hormones in these two distinct groups of individuals there were some differences in perceived appetite ratings. Most notably, the ORI experienced smaller fluctuations in hunger ratings. In addition, the TFEQ indicates that ORI may respond differently to hunger in that they are less likely to engage in dietary restraint and disinhibition behaviours. This style of eating could be an artifact of the differential response to the hormones or may be in response to some psychological factors or learned behaviour. Overeating and lack of response to satiety cues may be a learned response that affects some to a greater extent than others. Physiological signals and behavioural cues both regulate appetite and energy intake. Which one predominates may depend on a number of factors including genetics, the environment, past experiences, parental influence, sensory stimulation, social situation, and psychological well-being.
There are some limitations that should be considered when interpreting the results of this study. Firstly, the cross-sectional design of the study does not allow us to draw casual inferences and the sample size was relatively small. Further, given that ghrelin plasma concentrations differ throughout the day in cyclic fashion in relation to meal taking and diurnal rhythms [
In conclusion, comparing people who remain lean despite living in an obesegenic environment (ORI) to those who struggle to maintain a healthy weight (OSI) has provided us with a novel approach to investigate the aetiology of obesity. Given the differential body weights observed in the two study groups in the present study, a similar ghrelin concentration was unexpected. This could indicate that OSI respond differently to the same ghrelin concentration. Conversely, the lower than expected fasting ghrelin levels observed in the ORI may provide a protective mechanism that enables these individuals to remain lean. This warrants further investigation. The higher levels of dietary restriction and disinhibition amongst OSI indicate that psychosocial factors are likely also important regulators of energy balance in this group.
The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors would like to thank those who participated in the study. This project was funded by a University of Otago Research Grant.