Leptin was first characterized in 1994 (Zhang et al. 1994) and is one of the most important adipose tissue-derived hormones (Stanley et al. 2005). Leptin is the product of the ob gene which is predominantly expressed in adipocytes (Zhang et al. 1994), but also in gastric epithelium (Bado et al. 1998) and placenta (Masuzaki et al. 1997). The name 'leptin' has its roots in the Greek word 'leptos', meaning thin, and leptin was initially viewed as an adipocyte-derived signal that functions primarily to prevent obesity (Flier 2004). Indeed, the effects of leptin on energy homeostasis are well documented: exogenous leptin administration, both centrally and peripherally reduces food intake and increases energy expenditure (Friedman and Halaas 1998; Rosenbaum and Leibel 1998; Kershaw and Flier 2004). Adipocytes secrete leptin, however, in direct proportion to adipocyte size, and the majority of obese animals and humans have increased plasma leptin instead of an absolute or relative leptin deficiency (Kershaw and Flier 2004). Furthermore, short-term fasting results in a larger suppression of circulating leptin than would be expected from the loss of fat mass alone (Dubuc et al. 1998; Mars et al. 2005, 2006). A more recent concept proposes that a decrease in plasma leptin concentration might serve as an important signal from fat to brain informing the brain that the body is starving. Consequently, in the absence of leptin, the brain senses energy deficiency despite massive obesity and thus leptin's primary role may be as a hormone of starvation rather than one of plenty (Flier 2004).
Leptin signals via a single-transmembrane-domain receptor. Alternative mRNA splicing and post-translational processing results in multiple iso-forms of the receptor (Ob-R), such as the long, short and secreted form of the Ob-R (Stanley et al. 2005). Many effects of leptin on food intake and energy expenditure are mediated primarily via hypothalamic pathways. It is therefore hardly surprising that the long form of the Ob-R is expressed widely within the hypothalamus, in particular in the arcuate nucleus (ARC), but also in areas of the brain stem that are involved in the control of food intake. Two major types of ARC neurons carry the long form of the Ob-R: (1) neurons expressing the orexigenic neuropeptides neuropeptide Y (NPY) and agouti-related peptide (AgRP), and (2) neurons expressing proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART). Through the Ob-R, leptin inhibits the activity of orexigenic NPY/AgRP neurons and activates anorectic POMC/CART neurons. The absence of leptin action has profound effects on body weight. Lack of circulating leptin or of functional leptin receptors due to mutations in the pertinent genes leads to hyperphagia, obesity and neuroendocrine disturbances. This holds for the leptin- or leptin receptor-deficient ob/ob or db/db mouse, but also for genetic leptin deficiency in humans. The lack of leptin phenotype can be ameliorated by administration of exogenous leptin (Stanley et al. 2005). Finally, leptin has many functions besides control of energy homeostasis: it regulates the onset of puberty, promotes proliferation and differentiation of hematopoic cells, alters cytokine production by immune cells, stimulates endothelial cell growth and angiogenesis, and accelerates wound healing (Kershaw and Flier 2004).
Adiponectin, also called adipocyte complement-related protein (Acrp30) or adipose most abundant gene transcript (apM1), is a protein hormone with circulating blood levels that are up to 1000-fold higher than those of other hormones such as leptin and insulin (Stanley et al. 2005).
The exact function of adiponectin is largely unknown, but it is postulated to regulate energy homeostasis (Stanley et al. 2005): peripheral administration of adiponectin to rodents has been shown to attenuate body weight gain by increasing oxygen consumption without affecting food intake (Berg et al. 2001; Fruebis et al. 2001; Yamauchi et al. 2001; Yang et al. 2001). The plasma concentration of adiponectin is inversely correlated with adiposity in primates (Hotta et al. 2001) including humans (Yang et al. 2001; Faraj et al. 2003). Furthermore, plasma adiponectin increases during food restriction in rodents (Berg et al. 2001) including after weight loss induced by a calorie-restricted diet (Hotta et al. 2000) or gastric partition surgery in obese humans (Yang et al. 2001).
Plasma adiponectin levels correlate negatively with insulin resistance (Hotta et al. 2001), and adiponectin knock-out mice demonstrate severe diet-induced insulin resistance (Stanley et al. 2005), suggesting that adipo-nectin improves insulin sensitivity. Recently, two distinct adiponectin receptors have been cloned: adipoR1, which is highly expressed in skeletal muscle, and adipoR2, which is highly expressed in the liver. Adiponectin receptors have also been detected in the hypothalamus (Qi et al. 2004). All in all, adiponectin or potent adipoR agonists might have potential for the treatment of diabetes and obesity.
Resistin was identified in 2001 (Steppan et al. 2001), and rodent studies confirmed its adipose tissue-specific expression. Circulating resistin is increased in obese rodents (Rajala et al. 2004) and it appears to increase insulin resistance (Steppan et al. 2001; Banerjee and Lazar 2003). Mice lacking resistin have similar body weight as wild-type mice, but they exhibit lower blood glucose levels after fasting, due to reduced hepatic glucose production (Banerjee et al. 2004). Recently, Graveleau et al. (2005) demonstrated that resistin directly impaired glucose transport in primary mouse cardiomyocytes. All these findings suggest that resistin contributes to the development of insulin resistance in obese rodents. Nevertheless, whether resistin also plays a role in human obesity and diabetes is still unclear (Banerjee and Lazar 2003).
Acylation-stimulating protein (ASP) is produced in white adipose tissue and its synthesis requires three proteins: C3, adipsin and factor B (Faraj et al. 2004). ASP promotes fatty acid uptake and TAG synthesis, and it decreases lipolysis and FFA release from adipocytes (Cianflone et al. 2003). ASP-deficient mice are hyperphagic, but their energy expenditure is increased resulting in reduced body fat compared with wild-type mice (Xia et al. 2004). Also, these mice are resistant to diet-induced weight gain (Rajala and Scherer 2003). Several human studies indicate that ASP positively correlates with adiposity and insulin resistance (Cianflone et al. 2003). Consistent with this finding, plasma ASP levels decrease with body weight loss (Faraj et al. 2003).
Adipocytes are a predominant source of tumor necrosis factor a (TNF-a) and express both types of TNF-a receptors (Faraj et al. 2004). The association of TNF-a with type 2 diabetes and insulin resistance is well documented (Hotamisligil et al. 1993; Ruan and Lodish 2003), and mice lacking TNF-a function are protected from obesity-induced insulin resistance (Uysal et al. 1997). TNF-a reduces insulin signaling in many peripheral tissues such as liver, muscles and white adipose tissue (Faraj et al. 2004). In adipose tissue, TNF-a represses genes involved in the uptake and storage of FFA and lipogenesis, whereas it increases expression of genes favoring FFA and cytokine release (Ruan et al. 2002). In humans, weight loss decreased circulating TNF-a, but plasma levels of TNF-a did not correlate with measures of insulin resistance (Bruun et al. 2003), and systemic administration of a TNF-a antibody failed to improve insulin sensitivity in obese subjects with established type 2 diabetes (Ofei et al. 1996). Therefore, in contrast to rodents, it is not so clear that TNF-a contributes to obesity-induced insulin resistance in humans (Faraj et al. 2004).
Interleukin-6 (Il-6) is produced by a number of cells, including monocytes, endothelial cells, smooth muscle cells and adipocytes (Faraj et al. 2004). Up to 35% of the basal supply of Il-6 is derived from white adipose tissue (Mohamed-Ali et al. 1997). In obese male subjects, plasma levels of Il-6 were increased and correlated with measures of insulin resistance (Bruun et al. 2003). These findings appear to suggest a causal role for Il-6 in obesity and insulin resistance (Kershaw and Flier 2004). In contrast to this assumption, however, mice with targeted deletion of Il-6 develop mature-onset obesity and display impaired glucose clearance (Wallenius et al. 2002), whereas over-expression of Il-6 in pancreatic cells of non-obese diabetic mice resulted in delayed onset of diabetes mellitus and prolonged survival (Dicosmo et al. 1994). Therefore, increased Il-6 plasma levels may be a consequence rather than a cause of obesity and may be an attempt to prevent metabolic perturbations (Faraj et al. 2004). At the moment it is unclear whether IL-6 mimetic or antagonizing strategies may achieve a role in treating metabolic diseases.
This brief summary of some important factors produced and secreted by adipose tissue highlights the importance of adipose tissue as an endocrine organ playing a major role in energy homeostasis. It can be expected that even more genes expressed in adipose tissue will be identified and characterized in the future, and that these discoveries will promote our understanding of the role of adipose tissue at the crossroads of energy balance regulation, obesity and inflammation.
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