Obesity and insulin resistance (original) (raw)
Adipocytes are well known for their essential role as energy storage depots for triglycerides, from which energy is called forth at times of need in the form of FFAs and glycerol. However, data emerging over the past several years have established an additional role for the adipocyte, that of secretory cell (Figure 2). Adipocytes express and secrete numerous peptide hormones and cytokines, including TNF-α; plasminogen-activator inhibitor-1, which helps maintain hemostasis; angiotensinogen, whose proteolytic product regulates vascular tone; and leptin, which plays a central role in regulating energy balance. Adipose tissue can also produce active steroid hormones, including estrogen and cortisol (30, 31). Through such secreted products, adipocytes possess the capacity to influence local adipocyte biology, as well as systemic metabolism at sites as diverse as brain, liver, muscle, β cells, gonads, lymphoid organs, and systemic vasculature. This realization raises many possibilities for additional links between adipose function or mass and insulin resistance, independent of the adipocyte’s roles in energy storage and release (Figure 1).
Evolving view of the biological functions of the adipocyte. Previously, adipocytes were considered to be inert storage depots releasing fuel as fatty acids and glycerol in time of fasting or starvation. More recently it has become clear that adipocytes are endocrine glands that secrete important hormones, cytokines, vasoactive substances, and other peptides. ANS, autonomic nervous system.
A great deal of interest has followed the discovery that adipocytes express and secrete the cytokine TNF-α, and that enlarged adipocytes from obese animals and humans overexpress this factor (32). Although not all studies have found TNF-α to be elevated in obesity, the normal circulating levels of this factor are at the limit of detection, making quantitative analysis uncertain. This low expression may indicate that TNF-α acts in a paracrine rather than endocrine fashion. Alternative approaches to assessing a role of TNF-α in systemic insulin resistance are therefore needed, and in some but not all studies using neutralizing antibodies or other agents to block TNF-α function in animal models, it appears that such blockade heightens insulin sensitivity (33).
TNF-α has many effects on adipocyte function, and these include actions to inhibit lipogenesis and to increase lipolysis. These actions have been viewed by some as a feedback loop against excessive energy storage. Can excessive TNF-α cause insulin resistance? TNF-α signaling impairs insulin signaling, in part through serine phosphorylation of IRS-1 (32, 33), and can reduce GLUT4 gene expression, so a plausible cellular basis for TNF-α as a mediator of insulin resistance has been established. Further support derives from the beneficial effect of knockout of TNFα or TNFα receptor genes on insulin resistance in several animal models of obesity-associated insulin resistance (32, 33). However, improvement of insulin resistance in response to loss of TNF signaling is at best partial, and the effect of TNF neutralization has not been seen in all experimental models. Thus, TNF-α may be a partial contributor to insulin resistance, but other factors must exist.
Leptin, the product of the ob gene, may be one such factor. This adipocyte-derived hormone exerts pleiotropic effects, including profound effects on satiety, energy expenditure, and neuroendocrine function (34). The most compelling role of leptin from an evolutionary standpoint is its capacity to serve as a bidirectional signal that switches metabolic physiology and neuroendocrine status between programs appropriate to the fed and starved states. The proposed role for rising leptin as a strong (adipostatic) signal to prevent obesity is easily subverted by leptin resistance. Since increased energy stores would favor survival in periods of famine, the adipostatic aspect of leptin action may have been selected against during the course of evolution (35). This view of leptin as being primarily involved in the starvation/feeding switch does not negate the fact that the absence of leptin in both rodents and humans produces severe obesity for which leptin is clearly the cure. Nor does it lessen the importance of determining the molecular basis for leptin resistance, which limits the capacity of rising leptin to prevent obesity in most situations.
Severe insulin resistance is a well known feature of deficiency of leptin or its receptor in the ob/ob or db/db mouse strains, and these models were among the first to be investigated for the pathogenesis of insulin resistance in the early 1970s. Insulin resistance and hyperinsulinemia occur early in the life of these animals, are out of proportion to their adiposity at early stages, and exceed the insulin resistance and hyperinsulinemia due simply to hyperphagia and obesity. The degree to which diabetes (as opposed to insulin resistance without hyperglycemia) develops in these mice is determined by their genetic background, via effects on insulin secretory capacity and possibly other factors. The identity of these background modifier genes is unknown at present. Leptin’s major site of action is the hypothalamus, especially in selected nuclei within the ventrobasal hypothalamus, where neurons that are directly regulated by leptin reside (36). The fact that hyperinsulinemia and insulin resistance are produced by hypothalamic lesions affecting the ventromedial hypothalamic nucleus suggested a major role for the central nervous system (CNS) in regulation of insulin action or secretion. Consistent with this model, current evidence suggests that leptin exerts much of its effect on metabolism and satiety through actions within the ventrobasal hypothalamus.
The result of leptin replacement in ob/ob mice on diabetes and insulin resistance is dramatic. Leptin treatment causes both glucose and insulin levels to fall within hours of administration, before changes in either food intake or body weight occur, and prolonged leptin has effects on glucose and insulin that exceed those seen in pair-fed ob/ob mice (37). Leptin has a clear insulin-sensitizing effect acutely and also after chronic administration to normal rodents (37–39). The molecular basis for the insulin-sensitizing effect of leptin remains a topic of great interest. Two general views prevail. According to one, the metabolic actions of leptin are exerted predominantly through actions of leptin within the CNS, most likely within the hypothalamus (Figure 3). The hypothalamic pathways involved in these actions are incompletely understood, although a role for melanocortin signaling pathways has been suggested. These central effects may be transmitted to the periphery through a variety of mechanisms, including the effects of altered appetite to decrease nutrient flux into the body and the effects of leptin on neuroendocrine or neural pathways. Leptin’s effects on insulin sensitivity likely extend beyond those caused by alterations in food intake and nutrient flux, so actions via neuroendocrine or neural effectors are most likely involved as well. In many rodent models of obesity, including those due to leptin deficiency or resistance, increased glucocorticoids are an important mediator of both hyperphagia and insulin resistance, as seen through the beneficial effects of adrenalectomy (40). In ob/ob mice, leptin replacement suppresses the activated hypothalamic-pituitary-adrenocortical (HPA) axis, which may be an important component of leptin’s action on insulin sensitivity, at least in rodents. Autonomic nerves may also be involved, as suggested by the effects of denervation to reduce leptin’s action to promote glucose uptake into some muscle types (41). Major unanswered questions at this point include which signaling mechanism(s) and cellular targets in the periphery respond to the autonomic nerve output by which leptin affects metabolic pathways in relevant tissues, such as muscle, liver, and fat.
Leptin exerts multiple actions to regulate glucose homeostasis through autocrine, paracrine, endocrine, and neural circuits. Whereas many of leptin’s effects are mediated by the CNS, some effects may be exerted directly at the level of insulin target tissues or pancreatic islet cells.
The second view of how leptin sensitizes to insulin involves direct effects at the level of insulin target tissues (Figure 3). In addition to the actions of leptin to modify metabolism via the brain, substantial data support the notion that leptin may have important effects through direct action on peripheral target cells, including β cells, liver, muscle, and fat. Although initial surveys suggested that the ObRb isoform of the leptin receptor was not expressed in peripheral tissues, it now appears that receptor expression in such tissues occurs at biologically meaningful levels, as assessed by the ability to rapidly activate signaling events, including activation of STAT and MAPK pathways (42). Some evidence suggests that in tissues including muscle and β cells, leptin promotes lipid oxidation and inhibits lipid synthesis, which would promote insulin sensitivity (43, 44). Current data do not allow determination of the relative importance of central versus peripheral actions of leptin in the metabolic actions of the hormone with certainty. Since leptin fails to reverse insulin resistance and lipid accumulation in mice with ventromedial hypothalamic lesions, and low-dose central administration of leptin has major metabolic effects without changing blood leptin levels, it seems likely that central actions are required, and that without them, the peripheral actions are at best limited. Since leptin expression is induced in tissues such as skeletal muscle after periods of feeding, it is possible that leptin produced locally has important metabolic actions as well (45). Tissue-specific knockout of leptin receptor isoforms may be helpful in clarifying this point. Even if, as we suspect, leptin’s major actions are exerted within the CNS, we lack insight into the precise mechanism by which engaging central neural pathways rapidly changes the ability of leptin to regulate metabolic pathways in the periphery. This area will surely attract attention from the research community.
Unlike rodents, the few humans with leptin or leptin receptor mutations and obesity do not appear to have extraordinary degrees of insulin resistance, as assessed by hyperinsulinemia, and none have as yet been described with diabetes (46, 47). This difference may be related to the fact that in humans, unlike mice, leptin has little effect on the HPA axis. If leptin proves to have an important action on insulin sensitivity in humans, as it does in mice, then it will be important to determine the extent to which decreased leptin action, or leptin resistance, contributes to the insulin resistance of obesity in humans.