Obesity is the presence of excessive amount of adipose tissue. The excessive adipose tissue causes increased blood pressure, hepatic lipid synthesis, insulin resistance, and susceptibility to certain cancers. The anatomic location of the extra body fat has an important effect on the occurrence of these morbidities. Fat located in the intra-abdominal depot appears to convey greater metabolic risk than that in subcutaneous sites. The degree of fatness at which medically significant changes in these quantitative phenotypes occur is variable among individuals and, to some extent, ethnic groups. For example, obesity conveys greater risk of type 2 diabetes in Hispanics, African-Americans and Asians than in Caucasians. Advanced chronologic age may mitigate some of the adverse consequences of an otherwise excessive amount of body fat. For these reasons, no specific absolute amount or fractional content of body fat can be defined as pathologic for all individuals. Finally, adiposity and diminished “metabolic fitness” are not necessarily synonymous. Thus, individuals with high degrees of relative fatness can be physically fit and without apparent metabolic consequence of their adiposity if maintained—with exercise—at sufficient levels of aerobic and strength fitness. For actuarial and public health purposes, recently promulgated World Health Organization Expert Guidelines suggest that overweight and obesity be defined by body mass indices (BMI, a surrogate for adiposity, = Wt(kg)/[Ht(m)]2) of 25 and 30, respectively.
Studies of the concordance rates for adiposity among mono- and dizygous twins, and among adoptive children and their family members, and segregation and linkage and association studies, all point to a substantial contribution of genes to the determination of body composition in humans. Relatively rare instances of heritable syndromic obesity (Prader-Willi, Bardet-Biedl, etc.) are well known. More recently, rare mutations of human orthologs of some of the rodent single-gene obesity mutations have been identified (LEP, LEPR), as well as mutations in other genes that play a role in the control of body fat (e.g., POMC , MC4R, and PPARG). However, human obesity is complex and multigenic, with the penetrance of responsible genes showing strong dependence on environmental circumstance. The accelerating prevalence of obesity throughout the world, and especially in developed countries, must be the result of ever more “propitious” environmental circumstances that include high-caloric density foods and labor-saving technologies. The relevant genes determine an individual's adiposity relative to peers in the same environment.
Experiments in animals and humans point to a dependence of ingestive behavior, reproductive function, somatic growth, and carbohydrate homeostasis on the size of somatic fat stores. Body fat content is “defended” by a complex, coordinated series of metabolic and behavioral responses to reduction of body fat stores below a threshold that is determined by genetic and developmental factors. Clinical evidence of the existence of such regulatory mechanisms is the remarkable long-term constancy of body weight in adults. The average weight gain of 20 pounds between ages 25 and 55 years, considered in the context of energy intake of approximately 900,000 kcal per year, is +0.3 percent. Experimental weight perturbation in closely controlled experimental environment results in compensatory alterations in energy expenditure that can account for much of the relative constancy of body weight over time.
The neural networks and molecules that mediate control of body composition are now being elucidated. It is clear that the hypothalamus is the center for integration of vegetative endocrine and neural signals arising from adipose tissue, the gastrointestinal tract, various endocrine organs, autonomic nervous system, liver, and other parts of the brain. The hypothalamus also provides efferent signals to higher cortical centers, the brain stem/autonomic nervous system, and the anterior pituitary that affect food intake, energy expenditure, and the partitioning of nutrients between adipose and lean tissues. Within the brain, and especially nuclei of the hypothalamus, a series of orexigenic (NPY, Galanin, MCH, HCRT/Orexin, AGRP) and anorexigenic (MSH, CRF, urocortin, CART) peptides and their cognate receptors mediate the central nervous system processes related to energy homeostasis. Peripheral efferent signals providing information to the central nervous system regarding energy status include signals proportional to fat mass (leptin and possibly insulin) and gut-derived signals (CCK, glucagon, GLP1) stimulated by single meals. Very short-term neural signals that affect ingestive behavior may be provided by subtle fluctuations in circulating concentrations of glucose (and insulin), and by vagally mediated signals reflecting substrate flux across the gut and hepatic metabolic fuel disposition. The mechanism(s) by which long-term indicators of integrated energy homeostasis (such as leptin) bias short-term feeding decisions (meal size and frequency) is a critical question that remains unsolved.
The molecular physiology of weight regulation is profitably viewed through the lens of evolution. Body fat has important permissive effects on reproductive function, somatic growth, and the ability to breast feed progeny. Much of the neural circuitry and many of the molecules alluded to above, function to protect the organism against depletions of energy stores of sufficient severity to impair such critical physiological functions. The higher fractional body fat of females, in a teleological sense, prepares them for the energy costs of pregnancy and lactation. The system for weight regulation evolved in circumstances of restricted, intermittent access to calories, and the need for high levels of physical activity to acquire them. Thus, the system is designed to maximize energy storage, to invoke food seeking, and to reduce energy expenditure in circumstances when energy stores are deemed insufficient. The system is not designed primarily to protect against a phenotype—obesity—not likely to occur in the wild and that would not (unless very severe), either affect reproductive fitness or diminish life span in the reproductive years. The neural pathways and molecules with inhibitory effects on feeding are probably present to prevent the animal from unremitting ingestive behaviors that would interfere with other behaviors necessary for survival and reproduction.
Considerations such as those above, and an extensive series of physiological experiments, pointed to the existence of humoral signal(s) from adipose tissue that provide afferent information to the regulatory systems defending body fat content. The ob (obese) and db (diabetes) mouse mutations display physiologies consistent with this model. A positional cloning strategy was used to clone the ob gene whose gene product was named leptin. This molecule was used to identify its cognate receptor in a choroid plexus expression library. The receptor was shown to be the db gene. In this way, two important elements (an adipose tissue-derived signal and its hypothalamic receptor) in the regulatory pathway for body fat were identified. The molecular cloning of other rodent single-gene obesities (Yellow, tubby, fat) identified other molecules that are components of this system.
Leptin is a 146 amino acid peptide which is primarily produced in adipose tissue (but also in placenta and parietal cells of the stomach) and has structural homology to the cytokine family. The molecule is secreted into the blood in proportion to adipose tissue mass, is cleared primarily through the kidneys, and has many of the properties predicted for a feedback signal of somatic fat stores. When administered in the cerebral ventricles of mice and rats, leptin causes reduced food intake, increased energy expenditure (including increased physical activity), and suppresses insulin production while increasing skeletal muscle sensitivity to insulin. Deficiency of leptin action, due either to absence of the peptide (as in the ob mutation) or inability to detect the signal (as in the db mutation of the receptor) results in extreme obesity and infertility in both rodents and humans. In the hypothalamus, leptin causes coordinate changes in neuropeptide gene expression and release (decreased NPY and HCRT/Orexin; increased CRF, POMC, CART) that reduce food intake. Deficiency of leptin produces the opposite changes. That leptin is not the sole mediator of such responses to the status of energy stores is indicated by the fact that most of these same responses to energy deprivation occur in leptin- (or leptin receptor-) deficient animals.
The leptin receptor gene is a member of the cytokine receptor superfamily that includes the interleukin receptors and the growth hormone receptor. LEPR is spliced to at least 5 isoforms, of which the longest (1162 amino acids) is the only one that contains the STAT binding domain required for effects on nuclear transcription. The function of the other isoforms of LEPR is not clear, but the membrane bound isoform may serve as a transporter for leptin across the blood brain barrier, while a soluble isoform without a transmembrane domain, appears to be shed from cells and to act as a binding/transport protein for leptin. The Leprdb mouse has a mutation that interferes only with synthesis of the long form of the receptor. This defect alone is sufficient to produce a phenotype indistinguishable from a leptin deficient (Lepob ) mouse. The long isoform of LEPR functions as a homodimer expressed at highest levels in the hypothalamus. This isoform is expressed at much lower levels in cells outside the central nervous system, including in the pancreatic islets. The role of these peripheral receptors is not clear. Virtually all metabolic effects of leptin can be achieved via central nervous system administration of small amounts of the peptide.
The molecular cloning of the extant mouse single-gene obesity mutations, and the identification of many other genes related to energy intake ( NPY , CRF, HCRT/OREXIN, etc.), energy expenditure (UCP's) and energy partitioning (GH, LPL , INSULIN, PPARG, MYOSTATIN) have provided a rich resource for the investigation of the genetic bases for human energy homeostasis. In addition, the availability of reagents and analytic strategies for parametric and nonparametric mapping of phenotypes in human families has enabled the performance of linkage analyses for obesity in humans. In the aggregate, these studies suggest that most human obesity is the result of genetic predisposition mediated by polygenes interacting with the environment. The phenotype that is apparently inherited is adiposity relative to peers within a specific environment. The relevant genes, and allelic variants within them, probably vary among ethnic groups. Approximately 25 mouse quantitative trait loci (QTLs) for aspects of body composition and susceptibility to obesity when provided a high fat diet have been identified. Although no QTL has been cloned, some of them do map to regions of the mouse genome that also contain the major single-gene obesity loci. The same correspondence is noted when human obesity-related phenotypes—treated as qualitative or quantitative traits—are mapped in the human genome.
The medical treatment of obesity remains an area of enormous interest and importance, but disappointing efficacy. Based on the molecular physiology of body fat regulation, it is likely that any effective treatment will have to be continued indefinitely because the metabolic/behavioral resistance to maintenance of body composition below “normal” for each individual does not appear, in most instances, to abate with time. It is the maintenance of reduced body weight that is most difficult for patients to achieve. Behavior modification and drugs that suppress appetite by increasing activity at central noradrenergic and/or serotonergic neurons have limited long-term efficacy. Surgical reduction in gastric capacity has greater long-term efficacy, but carries risks related to surgery. The next generation of drugs—those that impair digestion of dietary fat or increase energy expenditure by activating β3-adrenoreceptors—are unlikely to have much better efficacy than those that have preceded them because, like their predecessors, they do not interfere with the relevant physiology so centrally as to subvert the compensatory changes that are invoked by alterations in energy intake or expenditure. The pharmacology of obesity at present is in a state similar to that for hypertension 30 years ago. Once the various etiologic mechanisms and contributing genes are better understood, more rational and effective long-term therapy will be possible.