Leptin (OB protein), the product of the adipose-specific ob gene, exerts important effects in the regulation of food intake and energy expenditure. Based upon results from animal studies, several groups have suggested that this action may be exerted in the brain, specifically in the hypothalamic region. However, to date, the localization of the OB-R in the human brain has not been described. One aim of this study was to contribute to a better understanding of the role that the central nervous system plays in the pathogenesis of obesity in humans. A first stage was to determine the OB-R expression in the human brain by means of immunohistochemistry and Western blotting. Several brain regions from 17 lean, 14 obese, and 4 diabetic (NIDDM) subjects, obtained from archival autopsy material, were sampled. Brain samples from neocortex, hypothalamus, medulla, limbic system, pineal and cerebellum were routinely processed in paraffin and analyzed with the avidin-biotin immunoperoxidase and diaminobenzidine detection method. Western blotting (WB) analysis was done on fresh brain tissue from an obese patient. Specific OB-R immunoreactivity was localized in the choroid plexus epithelium, ependymal lining, and neurons of the hypothalamic nuclei (arcuate, suprachiasmatic, mamillary, paraventricular, dorsomedial, supraoptic and posterior), nucleus basalis of Meynert, inferior olivary nuclei and cerebellar Purkinje cells. No differences in OB-R immunoreactivity were found among the three groups examined. WB analysis yielded 97- and 125-kD bands in the hypothalamus and cerebellum. In summary, this paper presents the first evidence to indicate the specific localization of the OB-R in the brain of lean, obese and NIDDM subjects.
To determine whether estrogen directly affects effective adipose lipolysis, palmitate rate of appearances ([14C]palmitate) was measured in 15 postmenopausal women. Each volunteer was studied after > or = 2 mo of estrogen treatment and again after > or = 2 mo of estrogen deficiency. Plasma hormone concentrations were controlled and identical on the 2 study days with use of the pancreatic clamp technique, and the lipolytic response to epinephrine and epinephrine + phentolamine was assessed. Results showed that overall palmitate flux was greater (10-20%, P < 0.05) during the estrogen-deficient than during the estrogen-replete study. Adrenergic stimulation of lipolysis was not specifically influenced by estrogen treatment, and control of plasma hormone concentrations did not eliminate the difference in palmitate flux between the estrogen-deficient and estrogen-replete study days. We conclude that estrogen deficiency is associated with increased plasma free fatty acid availability and that estrogen likely has direct, albeit small, effects on adipose tissue lipolysis.
We previously found that epinephrine, a mixed beta- and alpha-adrenoreceptor agonist, stimulates systemic and nonsplanchnic upper body free fatty acid (FFA) release but not lower body FFA release in healthy nonobese women. To evaluate the role of beta-adrenergic-mediated effects on this regional difference in lipolysis, we measured systemic, leg, and splanchnic FFA kinetics ([3H]palmitate) in seven healthy nonobese women before and during an intravenous isoproterenol infusion. Isoproterenol increased systemic palmitate flux (87 +/- 12 vs. 100 +/- 10 mumol/min, P < 0.05) but failed to affect leg [10.8 +/- 1.2 vs. 11.4 +/- 2.3 mumol/min, P = not significant (NS)] or splanchnic (10.8 +/- 3.2 vs. 10.0 +/- 1.8 mumol/min, P = NS) palmitate release. Upper body nonsplanchnic palmitate release increased from 56 +/- 14 to 71 +/- 10 mumol/min. Systemic O2 consumption increased (227 +/- 11 to 241 +/- 10 ml/min, P = 0.006) during isoproterenol infusion, as did leg (318 +/- 42 vs. 404 +/- 53 ml/min, P < 0.01) and splanchnic (827 +/- 104 vs. 970 +/- 108 ml/min, P < 0.05) plasma flow. These results suggest that lower body adipose tissue lipolysis in women is less sensitive or responsive than nonsplanchnic upper body adipose tissue to beta-adrenergic stimulation and that regional differences in alpha 2-adrenergic-receptor responses were not responsible for the similar regional differences we observed previously with epinephrine.
Abstract Adult humans have a remarkable sexual dimorphism in body shape. Men tend to store relatively more fat in the upper body whereas women store more fat in the lower body. We do not have a complete understanding of the mechanisms underlying these differences, but we know that people who preferentially store abdominal fat are at greater risk of metabolic disease. It is also known that the changes in sex steroid concentrations during puberty and again with advancing age are accompanied by changes in body fat distribution. The objective of this review is to describe what has been learned regarding the mechanisms underlying changes in regional body fat distribution that occur as a result of changes in sex hormones and to delineate effects of sex steroids in modulating body composition.
Aim: New-onset diabetes after kidney transplant (NODAT) adversely impacts kidney allograft and patient survival. Epigenetic alterations in adipose tissue like DNA methylation may play a contributory role. Methods: Adipose tissue DNA of the patients with NODAT and their age, sex and BMI matched controls (nine each) were sequenced by reduced representation bisulfite sequencing. Differentially methylated CpGs (DMCs) and differentially methylated regions (DMRs) were studied. Results: Adipose tissue from the patients had reduced DNA methylation in intergenic and intronic regions. DMCs were found to be more hypomethylated in repeat regions and hypermethylated in CGIs and promoter region. About 900 DMRs were found and their associated genes were significantly enriched in 32 pathways, the top ones of which were associated with insulin resistance and inflammation. Some DMR or DMC genes have known T2DM associations. Conclusion: Changes in DNA methylation in adipose tissue may be suggestive of future NODAT.
These studies were performed to determine whether protein turnover during exercise and after weight loss is influenced by obesity and body fat distribution. Leucine carbon flux was measured before, during, and after 2.5 h of bicycle exercise in 10 upper body obese, 9 lower body obese, and 6 nonobese, age-matched, premenopausal women. The obese women then followed an energy-restricted diet for 16 wk, resulting in approximately 8 kg weight loss. Baseline leucine carbon flux was greater (P < 0.01) in obese women than in nonobese women but decreased in a similar fashion in response to exercise in all groups. There were no differences between upper body and lower body obese women during exercise. After weight loss, baseline leucine carbon flux decreased (P < 0.05) similarly in both groups of obese women and was further suppressed by exercise. Thus obesity phenotype has no specific effect on either baseline protein turnover or the antiproteolytic response to moderate intensity exercise or weight loss. We conclude that the previously observed defect in insulin suppression of leucine flux in upper body obese women appears related to insulin resistance and does not represent an inherent abnormality of protein metabolism.
