Biomedical subjects

A S Greenberg

Publications and source records attributed to A S Greenberg.

At least 19 recordsLinked to original sources

PubMed2005

A retrospective analysis of medical or surgical therapy in young patients with diverticulitis.

BACKGROUND: Acute diverticulitis is increasingly being recognized in younger patients, but its management remains controversial. AIM: To compare long-term outcomes of young patients treated with surgery vs. medical therapy for their first episode of diverticulitis. METHODS: A retrospective chart analysis at a university and an affiliated community hospital between 1991 and 2002 revealed 149 patients < or = 40 years of age with confirmed diverticulitis. Forty-nine patients (38 males, 11 females) were contacted at least 1 year after their first episode of diverticulitis. Outcomes were compared based on initial therapy--antibiotics or surgical resection. The groups were compared by outcomes, gender, age, white blood cell count, temperature and diet. RESULTS: Three (15%) of 20 surgical patients (mean follow-up 6.89 years), and 16 (55%) of 29 medical patients had a recurrence of diverticulitis (mean follow-up 5.72 years; P = 0.01). The treatment groups did not differ in age, white blood cell count, or temperature. CONCLUSIONS: (i) Surgical treatment is effective initial therapy but disease may recur in a minority of patients; (ii) medical treatment is less effective initial therapy, with recurrence in half of the patients; (iii) initial presentation is not a strong predictor of disease recurrence.

Acute Disease↗

PubMed2004

Genetic variation at the perilipin (PLIN) locus is associated with obesity-related phenotypes in White women.

Perilipin coats intracellular lipid droplets and modulates adipocyte lipolysis. We have evaluated the association between several polymorphisms at the perilipin (PLIN) locus (PLIN1 : 6209T > C, PLIN4 : 11482G > A, PLIN5 : 13041A > G, and PLIN6 : 14995A > T) with obesity-related phenotypes in 1589 White subjects randomly selected from a general Spanish population. In women (n = 801), the less common alleles of PLIN1 and PLIN4, in strong linkage disequilibrium (D' : 0.96), were significantly associated with lower body mass index. Carriers of the allele 2 (6209C) at the PLIN1 locus weighed significantly less (-2.2 kg; p = 0.007) than women homozygotes for the wild-type genotype. The same was true for 11482A carriers at PLIN4 (p = 0.01). Moreover, the PLIN4 variant was associated with significantly lower waist-to-hip ratio, plasma glucose, and triacylglycerol concentrations. No significant associations with these obesity-related phenotypes were found in men. In agreement with these results, statistically significant gene-gender interactions were obtained when the risk of obesity was estimated (281 subjects were obese and 1308 non-obese). Only in women, PLIN1 and PLIN4 variant alleles (6209C and 11482A) were associated with a lower obesity risk [Odds ratio (OR) = 0.58, 95% confidence interval (CI): 0.38-0.93 and OR = 0.56, 95% CI: 0.36-0.89, respectively]. In summary, our data suggest that common alleles at the PLIN locus modulate body weight and metabolic variables in humans.

Adolescent↗

PubMed2002

Identifying the links between obesity, insulin resistance and beta-cell function: potential role of adipocyte-derived cytokines in the pathogenesis of type 2 diabetes.

A combination of insulin resistance and pancreatic beta-cell dysfunction underlies most cases of type 2 diabetes. While the interplay of these two impairments is believed to be important in the development and progression of type 2 diabetes, the mechanisms involved are unclear. A number of factors have been suggested as possibly linking insulin resistance and beta-cell dysfunction in the pathogenesis of type 2 diabetes mellitus. Pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNF-alpha) have deleterious effects on both glucose homeostasis and beta-cell function, and can disrupt insulin signalling pathways in both pancreatic beta cells and liver and adipose tissue. The anti-inflammatory activity of the thiazolidinedione anti-diabetic agents is potentially beneficial, given the possible role of pro-inflammatory cytokines in linking insulin resistance with beta-cell dysfunction.

Adipocytes↗

PubMed2001

Stimulation of lipolysis and hormone-sensitive lipase via the extracellular signal-regulated kinase pathway.

Hormonally stimulated lipolysis occurs by activation of cyclic AMP-dependent protein kinase (PKA) which phosphorylates hormone-sensitive lipase (HSL) and increases adipocyte lipolysis. Evidence suggests that catecholamines not only can activate PKA, but also the mitogen-activated protein kinase pathway and extracellular signal-regulated kinase (ERK). We now demonstrate that two different inhibitors of MEK, the upstream activator of ERK, block catecholamine- and beta(3)-stimulated lipolysis by approximately 30%. Furthermore, treatment of adipocytes with dioctanoylglycerol, which activates ERK, increases lipolysis, although MEK inhibitors decrease dioctanoylglycerol-stimulated activation of lipolysis. Using a tamoxifen regulatable Raf system expressed in 3T3-L1 preadipocytes, exposure to tamoxifen causes a 14-fold activation of ERK within 15-30 min and results in approximately 2-fold increase in HSL activity. In addition, when differentiated 3T3-L1 cells expressing the regulatable Raf were exposed to tamoxifen, a 2-fold increase in lipolysis is observed. HSL is a substrate of activated ERK and site-directed mutagenesis of putative ERK consensus phosphorylation sites in HSL identified Ser(600) as the site phosphorylated by active ERK. When S600A HSL was expressed in 3T3-L1 cells expressing the regulatable Raf, tamoxifen treatment fails to increase its activity. Thus, activation of the ERK pathway appears to be able to regulate adipocyte lipolysis by phosphorylating HSL on Ser(600) and increasing the activity of HSL.

3T3 Cells↗

PubMed2001

Identification of genes potentially involved in rupture of human atherosclerotic plaques.

Although rupture of an atherosclerotic plaque is the major cause of acute vascular occlusion, the exact molecular mechanisms underlying this process are still poorly understood. In this study, we used suppression subtractive hybridization to make an inventory of genes that are differentially expressed in whole-mount human stable and ruptured plaques. Two libraries were generated, one containing 3000 clones upregulated and one containing 2000 clones downregulated in ruptured plaques. Macroarray analysis of 500 randomly chosen clones showed differential expression of 45 clones. Among the 25 clones that showed at least a 2-fold difference in expression was the gene of perilipin, upregulated in ruptured plaques, and the genes coding for fibronectin and immunoglobulin lambda chain, which were downregulated in ruptured plaques. Reverse transcriptase-polymerase chain reaction analysis on 10 individual ruptured and 10 individual stable plaques showed a striking consistency of expression for the clones SSH6, present in 8 ruptured and 2 stable plaques, and perilipin, expressed in 8 ruptured plaques and completely absent in stable plaques. Localization studies of both perilipin mRNA and protein revealed expression in cells surrounding the cholesterol clefts and in foam cells of ruptured atherosclerotic plaques. No expression was observed in nondiseased artery, and only a few cells in the shoulder region of stable plaques tested positive for perilipin. In conclusion, this study shows that it is possible to identify genes that are differentially expressed in whole-mount stable or ruptured atherosclerotic plaques. This approach may yield several potential regulators of plaque destabilization.

Aged↗

PubMed2001

Sterol carrier protein-2 expression modulates protein and lipid composition of lipid droplets.

Despite the critical role lipid droplets play in maintaining energy reserves and lipid stores for the cell, little is known about the regulation of the lipid or protein components within the lipid droplet. Although immunofluorescence of intact cells as well as Western analysis of isolated lipid droplets revealed that sterol carrier protein-2 (SCP-2) was not associated with lipid droplets, SCP-2 expression significantly altered the structure of the lipid droplet. First, the targeting of fatty acid and cholesterol to the lipid droplets was significantly decreased. Second, the content of several proteins important for lipid droplet function was differentially increased (perilipin A), reduced severalfold (adipose differentiation-related protein (ADRP), vimentin), or almost completely eliminated (hormone-sensitive lipase and proteins >93 kDa) in the isolated lipid droplet. Third, the distribution of lipids within the lipid droplets was significantly altered. Double labeling of cells with 12-(N-methyl)-N-[(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-octadecanoic acid (NBD-stearic acid) and antisera to ADRP showed that 70, 24, and 13% of lipid droplets contained ADRP, NBD-stearic acid, or both, respectively. SCP-2 expression decreased the level of ADRP in the lipid droplet but increased the proportion wherein ADRP and NBD-stearic acid colocalized by 3-fold. SCP-2 expression also decreased the lipid droplet fatty acid and cholesterol mass (nmol/mg protein) by 5.2- and 6.6-fold, respectively. Finally, SCP-2 expression selectively altered the pattern of esterified fatty acids in favor of polyunsaturated fatty acids within the lipid droplet. Displacement studies showed differential binding affinity of ADRP for cholesterol and fatty acids. These data suggested that SCP-2 and ADRP play a significant role in regulating fatty acid and cholesterol targeting to lipid droplets as well as in determining their lipid and protein components.

4-Chloro-7-nitrobenzofurazan↗

PubMed2001

Distinct long-term regulation of glycerol and non-esterified fatty acid release by insulin and TNF-alpha in 3T3-L1 adipocytes.

AIMS/HYPOTHESIS: Adipose tissue lipolysis plays a central part in total body fuel metabolism. Our study was to assess the long-term regulation of glycerol and non-esterified fatty acid (NEFA) release by insulin or TNF-alpha. METHODS: Fully differentiated 3T3-L1 adipocytes were exposed for up to 22 h to insulin or TNF-alpha. RESULTS: Long-term insulin treatment resulted in increased basal glycerol release, reaching sixfold at 22 h with 1 nmol/l insulin. Partial inhibition was observed by pharmacologically inhibiting phosphatidylinositol 3-kinase or the mitogen-activated kinase kinase--extracellular signal-regulated kinase cascades. This represented 50-60% of the response induced by 1 nmol/l TNF-alpha and approximately 40 % of the glycerol release maximally stimulated by isoproterenol (1 micromol/l, 30 min). The cellular mechanism seemed to be distinct from that of TNF-alpha: First, glycerol release in response to long-term insulin was progressive with time and did not display a lag-time characteristic of the effect of TNF-alpha. Second, pretreatment and co-treatment of the cells with troglitazone greatly inhibited TNF-alpha-induced glycerol release (128.5 +/- 10.2 to 35.4 +/- 2.1 nmol/mg protein per h) but not the effect of insulin, which was exaggerated. Third, hormone-sensitive lipase protein content was decreased (45 %) by TNF-alpha but not following long-term insulin. Finally, TNF-alpha was associated with NEFA release to the medium, whereas long-term insulin treatment was not. Moreover, glycerol release during isoproterenol-stimulated lipolysis was additive to the effect of long-term insulin, whereas NEFA release was inhibited by nearly 90 %. CONCLUSIONS INTERPRETATION: Contradictory to its short-term inhibitory effect, long-term insulin stimulates glycerol release with concomitant stimulation of NEFA re-esterification.

3T3 Cells↗

PubMed2001

Parental selection of children's sexual orientation.

As we learn more about the causes of sexual orientation, the likelihood increases that parents will one day be able to select the orientation of their children. This possibility (at least that of selecting for heterosexuality) has generated a great deal of concern among supporters of homosexual rights, with such selection being widely condemned as harmful and morally repugnant. Notwithstanding this widespread condemnation, and even assuming, as we do, that homosexuality is entirely acceptable morally, allowing parents, by means morally unproblematic in themselves, to select for heterosexuality would be morally acceptable. This is because allowing parents to select their children's sexual orientation would further parent's freedom to raise the sort of children they wish to raise and because selection for heterosexuality may benefit parents and children and is unlikely to cause significant harm.

Adult↗

PubMed2001

The energy expenditure of postmenopausal women classified as restrained or unrestrained eaters.

OBJECTIVE: Restrained eating is a common dietary practice among individuals who are attempting to prevent weight gain, but little is known about differences in energy physiology and regulation between restrained and unrestrained eaters. We investigated this issue in non-obese free-living postmenopausal women classified as long-term restrained (n=26) or unrestrained (n=34) eaters group matched for body mass index (BMI). MEASUREMENTS: Measurements were made of total energy expenditure (TEE), resting energy expenditure (REE), body composition, reported leisure time activity, maximal aerobic capacity (VO2max) and weight change during the study period. In addition, physical activity level (PAL) and nonexercise activity thermogenesis (NEAT) were calculated from measured variables. RESULTS: There were no significant differences between the groups in body composition, weight change, aerobic capacity or total leisure time activity. Relationships between fat-free mass (FFM) and both REE and TEE, and the relationship between work load and energy expenditure in the test of maximal oxygen consumption, were also not different between groups. However, restrained eaters had a significantly lower PAL (equal to TEE/REE, 1.72+/-0.04 vs 1.84+/-0.04, P<0.05). In addition, in multiple regression models predicting NEAT, NEAT was significantly lower in restrained eaters than unrestrained eaters and there was a positive relationship between NEAT and weight change in unrestrained eaters but no relationship in restrained eaters (P<0.05). CONCLUSIONS: In contrast to a previous report, we found no significant difference in TEE between restrained and unrestrained eaters. PAL was slightly lower in restrained eaters, apparently due to reduced NEAT, and restrained eaters also lacked the positive association between NEAT and body weight change seen in unrestrained eaters. This latter finding, if confirmed in future studies, could help explain an increased susceptibility of restrained eaters to weight gain. SPONSORSHIP: NIH grants AG12829, DK46124 and T32AG00209, and US Cooperative Agreement number 58-1950-9-001.

Basal Metabolism↗

PubMed2001

Effects of a cereal rich in soluble fiber on body composition and dietary compliance during consumption of a hypocaloric diet.

OBJECTIVES: To investigate the effects of oats, a cereal rich in soluble fiber, on body composition changes and dietary compliance during consumption of a weight loss diet. METHODS: Subjects were 41 healthy men and women aged 18 to 78 years. Weight maintenance energy requirements were established over two weeks during consumption of a control diet with low soluble fiber content. Subjects then consumed a hypocaloric diet for six weeks, either consuming a low soluble fiber control diet or a diet containing 45 g/1000 kcal rolled oats, a whole grain cereal rich in soluble fiber (mean energy deficit -895+/-18 kcal/day relative to weight maintenance energy requirements). Changes in body fat and fat-free mass were determined by underwater weighing, and dietary compliance was assessed using the urinary osmolar excretion rate technique. In a final phase of the study, subjects ate ad libitum for six months, and changes in body weight and composition were monitored. RESULTS: There was no significant effect of the oat-containing diet on body weight or composition changes during the hypocaloric regimen or in the subsequent ad libitum period. In addition, fecal energy excretion was not significantly different between groups. However, there were non-significant trends indicating reduced hunger in the oat group compared to controls (frequency of hunger 2.5+/-0.5 vs. 3.6+/-0.4, P=0.1). In addition, fewer oat subjects were non-compliant (four versus seven subjects dropped out or had urinary osmolar excretions greater than 130% of values predicted from dietary intake), but again the difference was not significant. CONCLUSIONS: These results suggest that use of a cereal rich in soluble fiber in a closely monitored hypocaloric feeding regimen does not improve weight loss or dietary compliance. Further studies are needed to examine the possibility that cereals containing soluble fiber may have effects on hunger and dietary compliance that could be important in less tightly controlled protocols than the one described here.

Adult↗

PubMed2001

Metabolic, psychological, and health correlates of dietary restraint in healthy postmenopausal women.

BACKGROUND: Dietary restraint, a term used to describe the intentional control of food intake to prevent weight gain or promote weight loss, is commonly practiced by older adults, but little is known about its effects on physiology and metabolism. METHODS: We therefore compared a wide range of parameters between groups of healthy non-obese postmenopausal women classified psychometrically as unrestrained eaters (body mass index [BMI] 23.8 +/- 0.6 [SEM] kg/m(2), n = 28) or restrained eaters (BMI 24.5 +/- 0.5, n = 39). Measurements were made of reported micronutrient intakes, cardiopulmonary function, hematology, body temperature, skin thickness, bone mass, and immune function; in addition, self-perceived health, mood, and some dimensions of eating behavior were assessed by questionnaire. RESULTS: Macronutrient and micronutrient intakes were not significantly different between restrained and unrestrained eaters reporting energy intake to within 30% of predicted total energy expenditure. Restrained eaters had significantly lower hemoglobin (12.9 +/- 0.1 [SEM] vs 13.2 +/- 0.1 g/dl; p <.05), but values were within the normal range in both groups. In addition, restrained eaters scored significantly higher on the Eating Attitudes Test (p <.01) and drive-for-thinness (p <.001) and maturity fears (p <.05) subscores of the Eating Disorders Inventory, but values were again within the normal range. No other parameter differed significantly between groups. CONCLUSIONS: In this normal-weight population, restrained eating was not associated with detrimental effects in a wide range of physiological, metabolic, and health characteristics. Further work is needed to determine the relevance of these results to the general population.

Attitude to Health↗

PubMed2001

An oat-containing hypocaloric diet reduces systolic blood pressure and improves lipid profile beyond effects of weight loss in men and women.

Hypertension, dyslipidemia and overweight contribute substantially to cardiovascular disease risk. One of the most effective methods for improving high blood pressure and lipid profiles is loss of excess weight. Other recommendations for reducing cardiovascular risk include changes in dietary micronutrient, macronutrient and fiber intakes. To better define a diet for reduction in cardiovascular risk, 43 adults (body mass index 26.4 +/- 3.3, range 20.5-33.9 kg/m(2)) participated in an 8-wk study to determine the effects of two diets on weight, blood pressure, lipids and insulin sensitivity. For 2 wk, weight was maintained and all subjects consumed a control diet. For the next 6 wk, subjects consumed one of two hypocaloric diets (maintenance energy minus 4.2 MJ/d): the control diet (n = 21) or a diet containing oats [45 g/(4.2 MJ dietary energy. d), n = 22]. There was no significant difference between groups in changes in weight loss (control -4.0 +/- 1.1 kg, oats -3.9 +/- 1.6 kg, P = 0.8). The oats diet resulted in greater decreases in mean systolic blood pressure (oats -6 +/- 7 mm Hg, control -1 +/- 10 mm Hg, P = 0.026), whereas diastolic blood pressure change did not differ between the two groups (oats -4 +/- 6 mm Hg, control -3 +/- 5 mm Hg, P = 0.8). The oat diet resulted in significantly greater decreases in total cholesterol (oats -0.87 +/- 0.47 mmol/L, control -0.34 +/- 0.5 mmol/L, P = 0.003) and LDL cholesterol (oats -0.6 +/- 0.41 mmol/L, control -0.2 +/- 0.41mmol/L, P = 0.008). In summary, a hypocaloric diet containing oats consumed over 6 wk resulted in greater improvements in systolic blood pressure and lipid profile than did a hypocaloric diet without oats.

Adult↗

PubMed2001

An underfeeding study in healthy men and women provides further evidence of impaired regulation of energy expenditure in old age.

The effect of aging on energy regulation remains controversial. We compared the effects of underfeeding on changes in energy expenditure and respiratory quotient in young normal weight men and women [YNW, age 25.7 +/- 3.2 y(SD), body mass index (BMI) 23.1 +/- 1.6 kg/m(2)], young overweight men and women (YOW, age 26.1 +/- 3.5 y, BMI 27.7 +/- 2.1 kg/m(2)) and older (OLD) men and women (age 68.4 +/- 3.3 y, BMI 27.4 +/- 3.4 kg/m(2)). The thermic effect of feeding (TEF) during weight maintenance, and changes in resting energy expenditure (REE) and respiratory quotient were determined in response to undereating by an average 3.75 MJ/d for 6 wk. In addition, body composition was measured. No significant differences among the groups were observed in TEF, fasting and postprandial respiratory quotient, or the change in fasting respiratory quotient with underfeeding. However, REE adjusted for fat-free mass and fat mass was significantly lower in OLD subjects compared with YNW and YOW subjects (P < 0.05). In addition, the REE response to weight change was significantly attenuated in the OLD subjects (P = 0.023). These data suggest that the responsiveness of energy expenditure to negative energy balance is attenuated in old age, and provide further support for the hypothesis that mechanisms of energy regulation are broadly disregulated in old age.

Adult↗

PubMed2001

The HIV protease inhibitor nelfinavir induces insulin resistance and increases basal lipolysis in 3T3-L1 adipocytes.

HIV protease inhibitors (HPIs) are potent antiretroviral agents clinically used in the management of HIV infection. Recently, HPI therapy has been linked to the development of a metabolic syndrome in which adipocyte insulin resistance appears to play a major role. In this study, we assessed the effect of nelfinavir on glucose uptake and lipolysis in differentiated 3T3-L1 adipocytes. An 18-h exposure to nelfinavir resulted in an impaired insulin-stimulated glucose uptake and activation of basal lipolysis. Impaired insulin stimulation of glucose up take occurred at nelfinavir concentrations >10 micromol/l (EC(50) = 20 micromol/l) and could be attributed to impaired GLUT4 translocation. Basal glycerol and free fatty acid (FFA) release were significantly enhanced with as low as 5 micromol/l nelfinavir, displaying fivefold stimulation of FFA release at 10 micromol/l. Yet, the antilipolytic action of insulin was preserved at this concentration. Potential underlying mechanisms for these metabolic effects included both impaired insulin stimulation of protein kinase B Ser 473 phosphorylation with preserved insulin receptor substrate tyrosine phosphorylation and decreased expression of the lipolysis regulator perilipin. Troglitazone pre- and cotreatment with nelfinavir partly protected the cells from the increase in basal lipolysis, but it had no effect on the impairment in insulin-stimulated glucose uptake induced by this HPI. This study demonstrates that nelfinavir induces insulin resistance and activates basal lipolysis in differentiated 3T3-L1 adipocytes, providing potential cellular mechanisms that may contribute to altered adipocyte metabolism in treated HIV patients.

3T3 Cells↗

PubMed2000

Psychological measures of eating behavior and the accuracy of 3 common dietary assessment methods in healthy postmenopausal women.

BACKGROUND: Factors affecting the accuracy of reported energy intake (rEI) need to be identified. OBJECTIVE: Our objective was to investigate the association of psychological measures of eating behavior with the accuracy of rEI assessed by 7-d weighed intakes, a 24-h recall, and a food-frequency questionnaire. DESIGN: Subjects were 26 restrained eaters aged 60.3 +/- 0.6 y (mean +/- SEM) and weighing 63.8 +/- 1.7 kg and 34 unrestrained eaters aged 59.4 +/- 0.6 y and weighing 64.0 kg. rEI was assessed by using 3 dietary assessment methods and total energy expenditure (TEE) was determined by using doubly labeled water. Calculated EI (cEI) was determined as TEE corrected for the estimated change in body energy. Subjects completed the Eating Inventory. RESULTS: rEI values were significantly lower than TEE values for all 3 dietary assessment methods (P < 0.05); there was no significant relation between rEI and TEE by any method. There was no significant difference in 100 x rEI:TEE between restrained and unrestrained eaters by any of the dietary assessment methods. When combined data from the 3 methods were used, 100 x rEI:cEI was not significantly different from 100% in unrestrained eaters (99 +/- 6.8%) but was lower in restrained eaters (89.1 +/- 5.3%; P < 0.05). There was a positive relation between hunger and 100 x rEI:TEE (P < 0.05). CONCLUSIONS: Low hunger is associated with undereating relative to normal eating during measurement of dietary intake; high dietary restraint may be associated with a reduction in reporting of consumed foods. Dietary hunger and restraint assessed with use of the Eating Inventory may help to identify subjects likely to underreport dietary intake.

Body Weight↗

PubMed2000

Effects of a 6-week hypocaloric diet on changes in body composition, hunger, and subsequent weight regain in healthy young and older adults.

Recent studies have suggested a short-term impairment in the regulation of food intake in older adults, but further studies are needed to determine if a longer-term impairment exists and to identify underlying causes. Changes in body weight and composition were measured over a 6-week underfeeding study and a 6-month follow-up period in healthy young (n = 23) and older (OLD, n = 18) men and women. The young adults were either normal weight (YNW, n = 12) or overweight (YOW, n = 11). Energy intakes during underfeeding were 896 +/- 18 (SEM) kcal less than weight-maintenance energy requirements determined prior to underfeeding. In addition, changes in perceived hunger during underfeeding were monitored in a subgroup (n = 19). OLD and YOW subjects lost significantly more weight during underfeeding than did YNW subjects (p = .025 and .000, respectively), and they did not gain back significant weight in the 6-month follow-up. In addition, OLD subjects reported a significantly lower frequency of hunger during underfeeding (p = .05). There was no significant difference among groups in the relationship between weight lost and fat-free mass lost. Healthy OLD adults have an impaired ability to regulate food intake over at least 6 months following underfeeding compared with YNW adults, and a reduction in their perceived frequency of hunger may be a contributing factor.

Adult↗

PubMed1999

Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial.

CONTEXT: The protein hormone leptin is important to the homeostatic regulation of body weight. Treatment with exogenous leptin may affect weight loss. OBJECTIVE: To determine the relationship between increasing doses of exogenous leptin administration and weight loss in both lean and obese adults. DESIGN: A randomized, double-blind, placebo-controlled, multicenter, escalating dose cohort trial conducted from April 1997 to October 1998. SETTING: Four university nutrition and obesity clinics and 2 contract clinical research clinics. PARTICIPANTS: Fifty-four lean (body mass index, 20.0-27.5 kg/m2; mean [SD] body weight, 72.0 [9.7] kg) and 73 obese (body mass index, 27.6-36.0 kg/m2; mean [SD] body weight, 89.8 [11.4] kg) predominantly white (80%) men (n = 67) and women (n = 60) with mean (SD) age of 39 (10.3) years. INTERVENTIONS: Recombinant methionyl human leptin self-administered by daily morning subcutaneous injection (0 [placebo], 0.01, 0.03, 0.10, or 0.30 mg/kg). In part A, lean and obese subjects were treated for 4 weeks; in part B, obese subjects were treated for an additional 20 weeks. Lean subjects consumed a eucaloric diet to maintain body weight at the current value, and obese subjects were prescribed a diet that reduced their daily energy intake by 2100 kJ/d (500-kcal/d) from the amount needed to maintain a stable weight. MAIN OUTCOME MEASURES: Body weight, body fat, and incidence of adverse events. RESULTS: Weight loss from baseline increased with increasing dose of leptin among all subjects at 4 weeks (P = .02) and among obese subjects at 24 weeks (P = .01) of treatment. Mean (SD) weight changes at 4 weeks ranged from -0.4 (2.0) kg for placebo (n = 36) to -1.9 kg (1.6) kg for the 0.1 mg/kg dose (n = 29). Mean (SD) weight changes at 24 weeks ranged from -0.7 (5.4) kg for the 0.01 mg/kg dose (n = 6) to -7.1 (8.5) kg for the 0.30 mg/kg dose (n = 8). Fat mass declined from baseline as dose increased among all subjects at 4 weeks (P = .002) and among obese subjects at 24 weeks of treatment (P = .004); more than 95% of weight loss was fat loss in the 2 highest dose cohorts at 24 weeks. Baseline serum leptin concentrations were not related to weight loss at week 4 (P = .88) or at week 24 (P = .76). No clinically significant adverse effects were observed on major organ systems. Mild-to-moderate reactions at the injection site were the most commonly reported adverse effects. CONCLUSIONS: A dose-response relationship with weight and fat loss was observed with subcutaneous recombinant leptin injections in both lean and obese subjects. Based on this study, administration of exogenous leptin appears to induce weight loss in some obese subjects with elevated endogenous serum leptin concentrations. Additional research into the potential role for leptin and related hormones in the treatment of human obesity is warranted.

Adult↗

PubMed1999

Two ancient allelic lineages at the single classical class I locus in the Xenopus MHC.

Unlike all other vertebrates examined to date, there is only one detectable class I locus in the Xenopus MHC. On the bases of a nearly ubiquitous and high tissue expression, extensive polymorphism, and MHC linkage, this gene is of the classical or class Ia type. Sequencing analysis of class Ia cDNAs encoded by eight defined MHC haplotypes reveals two very old allelic lineages that perhaps emerged when humans and mice diverged from a common ancestor up to 100 million years ago. The unprecedented age of these lineages suggests that different class Ia genes from ancestors of the laboratory model Xenopus laevis are now expressed as alleles in this species. The lineages are best defined by their cytoplasmic and alpha2 peptide-binding domains, and there are highly diverse alleles (defined by the alpha1 peptide-binding domain) in each lineage. Surprisingly, the alpha3 domains are homogenized in both lineages, suggesting that interallelic gene conversion/recombination maintains the high sequence similarity.

Alleles↗