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Research paper thumbnail of Roles of Leptin and Ghrelin in the Loss of Body Weight Caused by a Low Fat, High Carbohydrate Diet

Roles of Leptin and Ghrelin in the Loss of Body Weight Caused by a Low Fat, High Carbohydrate Diet

Loss of body fat by caloric restriction is accompanied by decreased circulating leptin levels, in... more Loss of body fat by caloric restriction is accompanied by decreased circulating leptin levels, increased ghrelin levels, and increased appetite. In contrast, dietary fat restriction often decreases adiposity without increasing appetite. Substitution of dietary carbohydrate for fat has been shown to increase the area under the plasma leptin vs. time curve (AUC) over the course of 24 h. This effect, if sustained, could explain the absence of a compensatory increase in appetite on a low fat diet. To clarify the effect of dietary fat restriction on leptin and ghrelin, we measured AUC for these hormones in human subjects after each of the following sequential diets: 2 wk on a weight-maintaining 35% fat (F), 45% carbohydrate (C), 20% protein (P) diet (n = 18); 2 wk on an isocaloric 15% F, 65% C, 20% P diet (n = 18); and 12 wk on an ad libitum 15% F, 65% C, 20% P diet (n = 16). AUC for leptin was similar on the isocaloric 15% F and 35% F diets (555 +/- 57 vs. 580 +/- 56 ng/ml.24 h; P = NS). Body weight decreased from 74.6 +/- 2.4 to 70.8 +/- 2.7 kg on the ad libitum 15% F diet (P < 0.001) without compensatory increases in food consumption or AUC for ghrelin. Proportional amplitude of the 24-h leptin profile was increased after 12 wk on the 15% fat diet. We conclude that weight loss early in the course of dietary fat restriction occurs independently of increased plasma leptin levels, but that a later increase in amplitude of the 24-h leptin signal may contribute to ongoing weight loss. Fat restriction avoids the increase in ghrelin levels caused by dietary energy restriction.

Research paper thumbnail of Serum Ghrelin Levels Are Inversely Correlated with Body Mass Index, Age, and Insulin Concentrations in Normal Children and Are Markedly Increased in Prader-Willi Syndrome

Ghrelin, an endogenous ligand of the GH secretagogue receptor, stimulates appetite and causes obe... more Ghrelin, an endogenous ligand of the GH secretagogue receptor, stimulates appetite and causes obesity in animal models and in humans when given in pharmacologic doses. Prader-Willi Syndrome (PWS) is a genetic obesity syndrome characterized by GH deficiency and the onset of a voracious appetite and obesity in childhood. We, therefore, hypothesized that ghrelin levels may play a role in the expression of obesity in this syndrome. We measured fasting serum ghrelin levels in 13 PWS children with an average age of 9.5 yr (range, 5-15) and body mass index BMI) of 31.3 kg/m 2 (range, 22-46). The PWS group was compared with 4 control groups: 20 normal weight controls matched for age and sex, 17 obese children (OC), and 14 children with melanocortin-4 receptor mutations (MC4) matched for age, sex, and BMI, and a group of 3 children with leptin deficiency (OB). In non-PWS subjects, ghrelin levels were inversely correlated with age (r ‫؍‬ 0.36, P ‫؍‬ 0.007), insulin (r ‫؍‬ 0.55, P < 0.001), and BMI (r ‫؍‬ 0.62, P < 0.001), but not leptin. In children with PWS, fasting ghrelin concentrations were not significantly different compared with normal weight controls (mean ؎ SD; 429 ؎ 374 vs. 270 ؎ 102 pmol/liter; P ‫؍‬ 0.14). However, children with PWS did demonstrate higher fasting ghrelin concentrations (3-to 4-fold elevation) compared with all obese groups (OC, MC4, OB) (mean ؎ SD; 429 ؎ 374 vs. 139 ؎ 70 pmol/liter; P < 0.001). In conclusion, ghrelin levels in children with PWS are significantly elevated (3-to 4-fold) compared with BMI-matched obese controls (OC, MC4, OB). Elevation of serum ghrelin levels to the degree documented in this study may play a role as an orexigenic factor driving the insatiable appetite and obesity found in PWS. (J Clin Endocrinol Metab 88: 174 -178, 2003) Abbreviations: AGRP, Agouti-related protein; BMI, body mass index; CV, coefficients of variation; MC4, melanocortin-4; MC4-R, MC4 receptor; NC, normal weight children; NPY, neuropeptide Y; OB, children with leptin deficiency; OC, obese children; PWS, Prader-Willi Syndrome.

Research paper thumbnail of Ghrelin Levels Correlate with Insulin Levels, Insulin Resistance, and High-Density Lipoprotein Cholesterol, But Not with Gender, Menopausal Status, or Cortisol Levels in Humans

The gut peptide, ghrelin, may participate in the control of energy homeostasis and pituitary horm... more The gut peptide, ghrelin, may participate in the control of energy homeostasis and pituitary hormone secretion in humans, stimulating both food intake and, at pharmacological doses, ACTH and cortisol secretion. Meal consumption and weight loss regulate ghrelin levels, but less is known about the relationship of ghrelin to body composition, aging, menopausal status, and lipid metabolism. Therefore, 60 adult men and women of widely varying ages and weights were characterized in terms of body composition and levels of ghrelin, glucose, insulin, lipids, and cortisol. Fasting ghrelin levels correlated positively with age and negatively with BMI and fat cell size, but were not related to fat mass, intraabdominal fat, or lean mass. Fasting ghrelin levels correlated most strongly with insulin levels (r ‫؍‬ ؊0.39; P ‫؍‬ 0.002), insulin resistance as determined by the quantitative insulin sensitivity check index (r ‫؍‬ 0.38; P ‫؍‬ 0.003), and high-density lipoprotein cholesterol levels (r ‫؍‬ 0.33; P ‫؍‬ 0.009). Meal-induced ghrelin suppression correlated with the postprandial rise in insulin (r ‫؍‬ 0.39; P < 0.05). Ghrelin levels were similar in men and women and did not vary by menopausal status or in association with cortisol levels. Our data are consistent with the hypotheses that insulin may negatively regulate ghrelin and that high-density lipoprotein may be a carrier particle for circulating ghrelin. (J Clin Endocrinol Metab 88: 5747-5752, 2003)

Research paper thumbnail of Plasma Ghrelin Levels after Diet-Induced Weight Loss or Gastric Bypass Surgery

New England Journal of Medicine, 2002

Background Weight loss causes changes in appetite and energy expenditure that promote weight rega... more Background Weight loss causes changes in appetite and energy expenditure that promote weight regain. Ghrelin is a hormone that increases food intake in rodents and humans. If circulating ghrelin participates in the adaptive response to weight loss, its levels should rise with dieting. Because ghrelin is produced primarily by the stomach, weight loss after gastric bypass surgery may be accompanied by impaired ghrelin secretion.

Research paper thumbnail of A Preprandial Rise in Plasma Ghrelin Levels Suggests a Role in Meal Initiation in Humans

Diabetes, 2001

The recently discovered orexigenic peptide ghrelin is produced primarily by the stomach and circu... more The recently discovered orexigenic peptide ghrelin is produced primarily by the stomach and circulates in blood at levels that increase during prolonged fasting in rats. When administered to rodents at supraphysiological doses, ghrelin activates hypothalamic neuropeptide Y/agouti gene-related protein neurons and increases food intake and body weight. These findings suggest that ghrelin may participate in meal initiation. As a first step to investigate this hypothesis, we sought to determine whether circulating ghrelin levels are elevated before the consumption of individual meals in humans. Ghrelin, insulin, and leptin were measured by radioimmunoassay in plasma samples drawn 38 times throughout a 24-h period in 10 healthy subjects provided meals on a fixed schedule. Plasma ghrelin levels increased nearly twofold immediately before each meal and fell to trough levels within 1 h after eating, a pattern reciprocal to that of insulin. Intermeal ghrelin levels displayed a diurnal rhythm that was exactly in phase with that of leptin, with both hormones rising throughout the day to a zenith at 0100, then falling overnight to a nadir at 0900. Ghrelin levels sampled during the troughs before and after breakfast correlated strongly with 24-h integrated area under the curve values (r ‫؍‬ 0.873 and 0.954, respectively), suggesting that these convenient, single measurements might serve as surrogates for 24-h profiles to estimate overall ghrelin levels. Circulating ghrelin also correlated positively with age (r ‫؍‬ 0.701). The clear preprandial rise and postprandial fall in plasma ghrelin levels support the hypothesis that ghrelin plays a physiological role in meal initiation in humans.

Research paper thumbnail of Roles of Leptin and Ghrelin in the Loss of Body Weight Caused by a Low Fat, High Carbohydrate Diet

Roles of Leptin and Ghrelin in the Loss of Body Weight Caused by a Low Fat, High Carbohydrate Diet

Loss of body fat by caloric restriction is accompanied by decreased circulating leptin levels, in... more Loss of body fat by caloric restriction is accompanied by decreased circulating leptin levels, increased ghrelin levels, and increased appetite. In contrast, dietary fat restriction often decreases adiposity without increasing appetite. Substitution of dietary carbohydrate for fat has been shown to increase the area under the plasma leptin vs. time curve (AUC) over the course of 24 h. This effect, if sustained, could explain the absence of a compensatory increase in appetite on a low fat diet. To clarify the effect of dietary fat restriction on leptin and ghrelin, we measured AUC for these hormones in human subjects after each of the following sequential diets: 2 wk on a weight-maintaining 35% fat (F), 45% carbohydrate (C), 20% protein (P) diet (n = 18); 2 wk on an isocaloric 15% F, 65% C, 20% P diet (n = 18); and 12 wk on an ad libitum 15% F, 65% C, 20% P diet (n = 16). AUC for leptin was similar on the isocaloric 15% F and 35% F diets (555 +/- 57 vs. 580 +/- 56 ng/ml.24 h; P = NS). Body weight decreased from 74.6 +/- 2.4 to 70.8 +/- 2.7 kg on the ad libitum 15% F diet (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) without compensatory increases in food consumption or AUC for ghrelin. Proportional amplitude of the 24-h leptin profile was increased after 12 wk on the 15% fat diet. We conclude that weight loss early in the course of dietary fat restriction occurs independently of increased plasma leptin levels, but that a later increase in amplitude of the 24-h leptin signal may contribute to ongoing weight loss. Fat restriction avoids the increase in ghrelin levels caused by dietary energy restriction.

Research paper thumbnail of Serum Ghrelin Levels Are Inversely Correlated with Body Mass Index, Age, and Insulin Concentrations in Normal Children and Are Markedly Increased in Prader-Willi Syndrome

Ghrelin, an endogenous ligand of the GH secretagogue receptor, stimulates appetite and causes obe... more Ghrelin, an endogenous ligand of the GH secretagogue receptor, stimulates appetite and causes obesity in animal models and in humans when given in pharmacologic doses. Prader-Willi Syndrome (PWS) is a genetic obesity syndrome characterized by GH deficiency and the onset of a voracious appetite and obesity in childhood. We, therefore, hypothesized that ghrelin levels may play a role in the expression of obesity in this syndrome. We measured fasting serum ghrelin levels in 13 PWS children with an average age of 9.5 yr (range, 5-15) and body mass index BMI) of 31.3 kg/m 2 (range, 22-46). The PWS group was compared with 4 control groups: 20 normal weight controls matched for age and sex, 17 obese children (OC), and 14 children with melanocortin-4 receptor mutations (MC4) matched for age, sex, and BMI, and a group of 3 children with leptin deficiency (OB). In non-PWS subjects, ghrelin levels were inversely correlated with age (r ‫؍‬ 0.36, P ‫؍‬ 0.007), insulin (r ‫؍‬ 0.55, P < 0.001), and BMI (r ‫؍‬ 0.62, P < 0.001), but not leptin. In children with PWS, fasting ghrelin concentrations were not significantly different compared with normal weight controls (mean ؎ SD; 429 ؎ 374 vs. 270 ؎ 102 pmol/liter; P ‫؍‬ 0.14). However, children with PWS did demonstrate higher fasting ghrelin concentrations (3-to 4-fold elevation) compared with all obese groups (OC, MC4, OB) (mean ؎ SD; 429 ؎ 374 vs. 139 ؎ 70 pmol/liter; P < 0.001). In conclusion, ghrelin levels in children with PWS are significantly elevated (3-to 4-fold) compared with BMI-matched obese controls (OC, MC4, OB). Elevation of serum ghrelin levels to the degree documented in this study may play a role as an orexigenic factor driving the insatiable appetite and obesity found in PWS. (J Clin Endocrinol Metab 88: 174 -178, 2003) Abbreviations: AGRP, Agouti-related protein; BMI, body mass index; CV, coefficients of variation; MC4, melanocortin-4; MC4-R, MC4 receptor; NC, normal weight children; NPY, neuropeptide Y; OB, children with leptin deficiency; OC, obese children; PWS, Prader-Willi Syndrome.

Research paper thumbnail of Ghrelin Levels Correlate with Insulin Levels, Insulin Resistance, and High-Density Lipoprotein Cholesterol, But Not with Gender, Menopausal Status, or Cortisol Levels in Humans

The gut peptide, ghrelin, may participate in the control of energy homeostasis and pituitary horm... more The gut peptide, ghrelin, may participate in the control of energy homeostasis and pituitary hormone secretion in humans, stimulating both food intake and, at pharmacological doses, ACTH and cortisol secretion. Meal consumption and weight loss regulate ghrelin levels, but less is known about the relationship of ghrelin to body composition, aging, menopausal status, and lipid metabolism. Therefore, 60 adult men and women of widely varying ages and weights were characterized in terms of body composition and levels of ghrelin, glucose, insulin, lipids, and cortisol. Fasting ghrelin levels correlated positively with age and negatively with BMI and fat cell size, but were not related to fat mass, intraabdominal fat, or lean mass. Fasting ghrelin levels correlated most strongly with insulin levels (r ‫؍‬ ؊0.39; P ‫؍‬ 0.002), insulin resistance as determined by the quantitative insulin sensitivity check index (r ‫؍‬ 0.38; P ‫؍‬ 0.003), and high-density lipoprotein cholesterol levels (r ‫؍‬ 0.33; P ‫؍‬ 0.009). Meal-induced ghrelin suppression correlated with the postprandial rise in insulin (r ‫؍‬ 0.39; P < 0.05). Ghrelin levels were similar in men and women and did not vary by menopausal status or in association with cortisol levels. Our data are consistent with the hypotheses that insulin may negatively regulate ghrelin and that high-density lipoprotein may be a carrier particle for circulating ghrelin. (J Clin Endocrinol Metab 88: 5747-5752, 2003)

Research paper thumbnail of Plasma Ghrelin Levels after Diet-Induced Weight Loss or Gastric Bypass Surgery

New England Journal of Medicine, 2002

Background Weight loss causes changes in appetite and energy expenditure that promote weight rega... more Background Weight loss causes changes in appetite and energy expenditure that promote weight regain. Ghrelin is a hormone that increases food intake in rodents and humans. If circulating ghrelin participates in the adaptive response to weight loss, its levels should rise with dieting. Because ghrelin is produced primarily by the stomach, weight loss after gastric bypass surgery may be accompanied by impaired ghrelin secretion.

Research paper thumbnail of A Preprandial Rise in Plasma Ghrelin Levels Suggests a Role in Meal Initiation in Humans

Diabetes, 2001

The recently discovered orexigenic peptide ghrelin is produced primarily by the stomach and circu... more The recently discovered orexigenic peptide ghrelin is produced primarily by the stomach and circulates in blood at levels that increase during prolonged fasting in rats. When administered to rodents at supraphysiological doses, ghrelin activates hypothalamic neuropeptide Y/agouti gene-related protein neurons and increases food intake and body weight. These findings suggest that ghrelin may participate in meal initiation. As a first step to investigate this hypothesis, we sought to determine whether circulating ghrelin levels are elevated before the consumption of individual meals in humans. Ghrelin, insulin, and leptin were measured by radioimmunoassay in plasma samples drawn 38 times throughout a 24-h period in 10 healthy subjects provided meals on a fixed schedule. Plasma ghrelin levels increased nearly twofold immediately before each meal and fell to trough levels within 1 h after eating, a pattern reciprocal to that of insulin. Intermeal ghrelin levels displayed a diurnal rhythm that was exactly in phase with that of leptin, with both hormones rising throughout the day to a zenith at 0100, then falling overnight to a nadir at 0900. Ghrelin levels sampled during the troughs before and after breakfast correlated strongly with 24-h integrated area under the curve values (r ‫؍‬ 0.873 and 0.954, respectively), suggesting that these convenient, single measurements might serve as surrogates for 24-h profiles to estimate overall ghrelin levels. Circulating ghrelin also correlated positively with age (r ‫؍‬ 0.701). The clear preprandial rise and postprandial fall in plasma ghrelin levels support the hypothesis that ghrelin plays a physiological role in meal initiation in humans.