Background Leptin, the product of the ob gene, is a hormone secreted by adipocytes. Animals with mutations in the ob gene are obese and lose weight when given leptin, but little is known about the physiologic actions of leptin in humans. Methods Using a newly developed radioimmunoassay, we measured serum concentrations of leptin in 136 normal-weight subjects and 139 obese subjects (body-mass index, >27.3 for men and >27.8 for women; the body-mass index was defined as the weight in kilograms divided by the square of the height in meters). The measurements were repeated in seven obese subjects after weight loss and during maintenance of the lower weight. The ob messenger RNA (mRNA) content of adipocytes was determined in 27 normal-weight and 27 obese subjects. Results The mean (±SD) serum leptin concentrations were 31.3±24.1 ng per milliliter in the obese subjects and 7.5±9.3 ng per milliliter in the normal-weight subjects (P<0.001). There was a strong positive correlation between serum leptin concentration...

Serum Immunoreactive-Leptin Concentrations in Normal-Weight and Obese Humans

Leptin, the gene product of the obese gene, may play an important role in regulating body weight by signalling the size of the adipose tissue mass. Plasma leptin was found to be highly correlated with body mass index (BMI) in rodents and in 87 lean and obese humans. In humans, there was variability in plasma leptin at each BMI suggesting that there are differences in its secretion rate from fat. Weight loss due to food restriction was associated with a decrease in plasma leptin in samples from mice and obese humans.

Leptin levels in human and rodent : Measurement of plasma leptin and ob RNA in obese and weight-reduced subjects

Identification and expression cloning of a leptin receptor Ob-R

Methods for assessment, e.g., anthropometric indicators and imaging techniques, of several phenotypes of human obesity, with special reference to abdominal fat content, have been evaluated. The correlation of fat distribution with age, gender, total body fat, energy balance, adipose tissue lipoprotein lipase and lipolytic activity, adipose tissue receptors, and genetic characteristics are discussed. Several secreted or expressed factors in the adipocyte are evaluated in the context of fat tissue localization. The body fat distribution and the metabolic profile in nonobese and obese individuals is discussed relative to lipolysis, antilypolysis and lipogenesis, insulin sensitivity, and glucose, lipid, and protein metabolism. Finally, the endocrine regulation of abdominal visceral fat in comparison with the adipose tissue localized in other areas is presented.

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Subcutaneous and visceral adipose tissue : Their relation to the metabolic syndrome

Various aspects of the complex spatio-temporal patterning of hypothalamic signaling that leads to the development of synchronized nocturnal feeding in the rat are critically examined. Undoubtedly, as depicted in Fig. 7, a distinct ARN in the hypothalamus is involved in the control of nocturnal appetite. At least four basic elements operate within this ARN. These are: 1) A discrete appetite-driving or orexigenic network of NPY, NE, GABA, GAL, EOP, and orexin transduces and releases appetite-stimulating signals. 2) Similarly, anorexigenic signal-producing pathways (e.g., CRH, GLP-1, alpha MSH, and CART) orchestrate neural events for dissipation of appetite and to terminate feeding, possibly by interrupting NPY efflux and action at a postsynaptic level within the hypothalamus. It is possible that some of these may represent the physiologically relevant "off" switches under the influence of GABA alone, or AgrP alone, or in combination with NPY released from the NPY-, GABA-, and AgrP-coproducing neurons. 3) Recent evidence shows that neural elements in the VMN-DMN complex tonically restrain the orexigenic signals during the intermeal interval; the restraint is greatly aided by leptin's action via diminution of orexigenic (NPY) and augmentation of anorexigenic (GLP-1, alpha MSH, and CART) signals. Since interruption of neurotransmission in the VMN resulted in hyperphagia and development of leptin resistance, it seems likely that the VMN is an effector site for the restraint exercised by leptin. The daily rhythms in leptin synthesis and release are temporally dissociable because the onset of daily rise in leptin gene expression in adipocytes precedes that in leptin secretion. Nevertheless, these rhythms are in phase with daily ingestive behavior because the peak in circulating leptin levels occurs during the middle of the feeding period. These observations, coupled with the fact that circulating levels of leptin are directly related to adiposity, pose a new challenge for elucidating the precise role of leptin in daily patterning of feeding in the rat. 4) A neural timing mechanism also operates upstream from the ARN in the daily management of energy homeostasis. Although the precise anatomical boundaries are not clearly defined, this device is likely to be composed of a group of neurons that integrate incoming internal and external information for the timely onset of the drive to eat. Evidently, this network operates independently in primates, but it is entrained to the circadian time keeper in the SCN of rodents. Apart from its role in the onset of drive to eat, the circadian patterns of gene expression of NPY, GAL, and POMC denote independent control of the timing device on the synthesis and availability for release of orexigenic signals. The VMN-DMN-PVN complex is apparently an integrated constituent of the timing mechanism in this context, because lesions in each of these sites result in loss of regulated feeding. The accumulated evidence points to the PVN and surrounding neural sites within this framework as the primary sites of release and action of various orexigenic and anorexigenic signals. A novel finding is the identification of the interconnected wiring of the DMN-mPVN axis that may mediate leptin restraint on NPY-induced feeding. The chemical phenotypes of leptin and NPY target neurons in this axis remain to be identified. These multiple orexigenic and anorexigenic pathways in the hypothalamic ARN appear to represent redundancy, a characteristic of regulated biological systems to provide a "fail-safe" neural mechanism to meet an organism's constant energy needs for growth and maintenance. Within this formulation, the coexisting orexigenic signals (NPY, NE, GAL, GABA, and AgrP) represent either another level of redundancy or it is possible that these signals operate within the ARN as reinforcing agents to varying degrees under different circumstances. (ABSTRACT TRUNCATED)

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Interacting appetite-regulating pathways in the hypothalamic regulation of body weight.

Obesity presents a significant challenge to the general health of affluent nations in terms of the number of people affected, the serious associated maladies and the lack of effective treatments. While common wisdom has held that obesity results from 'gluttony and sloth', a number of studies have indicated physiological causes of underlying the pathogenesis of obesity, with the degree of adiposity having a strong genetic component. Recently, the obese gene in the ob/ob mouse was cloned, along with its human homologue. The specific production of the obese protein by adipose tissue suggested that it may function in a feedback loop from fat tissue to the hypothalamus to control energy intake and/or energy expenditure, and that it may play a role in the pathogenesis of human obesity. In this study we report that obese mRNA expression is elevated in ex vivo omental adipocytes isolated from massively obese humans in the absence of an identifiable mutation. Therefore, we speculate that this increased expression may suggest that the massively obese are insensitive to the putative regulatory function(s) of the obese gene product.

Diana Paglia

Papers

Increased obese mRNA expression in omental fat cells from massively obese humans.