phosphorylates key tyrosine residues within the cytoplasmic LepRb region (Y , Y , Y ), providing docking sites for binding of intra-cellular signalling components. In particular, STAT3 transcription factors bind to these activated SH2 domains at Y1138 and are phosphorylated, dimerised, and translocated to the nucleus where they alter transcription of target genes. Suppressor of cytokine signalling (SOCS3) is induced by pSTAT3 and acts to negatively regulate leptin signalling by inhibiting phosphorylation of the cytoplasmic tail of LepRb by JAK2

et al. 2001; Solovyova et al. 2009). The three tyrosine residues appear to define the pleiotropy of LepR signalling: Tyr985 is necessary and sufficient for activation of ERK, Tyr1077 can induce tyrosine phosphorylation of STAT5, whereas Tyr1138 is capable of phosphorylating STAT1, 3 and 5 (Hekerman et al. 2005).

6 Obesity and Leptin Resistance

The hope that leptin might be a "miracle cure" in the treatment of obesity was short lived. Rather than being leptin deficient, most obese humans and animals have high levels of circulating leptin (Maffei et al. 1995; Considine et al. 1996). The failure of elevated leptin levels to control or reverse obesity suggests the existence of a resistant state (Scarpace and Zhang 2009). Studies in humans showed that obese individuals exhibit high peripheral leptin levels but relatively lower cerebrospinal fluid (CSF) concentrations, indicating impaired transport of leptin from the peripheral to central sites (Caro et al. 1996; Schwartz et al. 1996). Rodent studies have subsequently demonstrated two distinct components to leptin resistance—a resistance to peripherally administered leptin suggesting a failure of the hormone to access CNS target sites and/or resistance to CNS leptin resulting from impaired responses in CNS neurons expressing LepR. Furthermore, leptin resistance is also considered a key and potentially causal component of obesity. There is evidence from outbred rat strains that inherent differences in leptin sensitivity prior to dietary manipulation may determine individual susceptibility to obesity (Levin et al. 2003, 2004). These and other data suggest that leptin resistance predisposes towards or promotes obesity, although the precise relationship and the underlying mechanisms remain to be resolved (see review by Scarpace and Zhang 2009). A particularly relevant observation is that all models of leptin resistance develop obesity on a high-fat diet, but only some show weight gain and increased body adiposity on a stock diet (Scarpace and Zhang 2009). This suggests a link between leptin resistance and the reward system-driven caloric over-consumption of palatable diets (as addressed in more detail, below).

In order to study the process of leptin resistance in obesity progression, DIO rodents are typically fed a high-energy diet, with a greater proportion of calories being derived from fat compared with chow-fed animals. These models have provided information on the rate of body weight changes induced by transfer to such a diet and in addition have revealed differences in terms of susceptibility to DIO between different mouse strains (Prpic et al. 2003) and within outbred rat strains (Levin et al. 1989; Archer et al. 2003; Enriori et al. 2007). The body weight responses, along with the progressive loss of leptin sensitivity during DIO progression, also resemble the human situation. Therefore, these animal models are of great use in the identification of pathways that are affected during DIO development. Experimental evidence has suggested that during DIO, there is a progressive loss of leptin responsiveness, involving an initial gain in adiposity whilst retaining responses to peripherally administered leptin, followed by a loss of peripheral leptin responsiveness, and finally resistance to both peripherally and centrally administered leptin (El-Haschimi et al. 2000).

Within the leptin signalling pathway, suppressor of cytokine signalling 3 (SOCS3) has emerged as a likely candidate in mediating hormone resistance. Following leptin receptor activation, SOCS3 is induced and acts to negatively regulate leptin signalling, as discussed above (Howard and Flier 2006). Elevated SOCS3 expression in the ARC is observed in DIO mice, and this is associated with a reduced sensitivity to the effect of leptin on food intake, body weight and neuropeptide secretion (Munzberg et al. 2004; Enriori et al. 2007). Neuron-specific removal (Mori et al. 2004) or heterozygous loss of SOCS3 (Howard et al. 2004) confers an enhanced response to leptin administration and a greater resistance to DIO.

The composition and origin of fat in the diet may influence not only the progression towards obesity but also leptin signalling. The direct effect of high-fat diet on leptin resistance may reflect the direct action of fatty acids, triglycerides and lipid molecules at leptin-sensitive neurons, a possible component of hypotha-lamic nutrient sensing (Jordan et al. 2010) or an effect on leptin transport across the blood-brain barrier (Banks et al. 2004). The picture emerging in high-fat diet-induced obesity is of leptin resistance both causing and resulting from obesity. Thus, high-fat diets can induce leptin resistance either directly in the absence of obesity or indirectly, secondary to obesity and resultant high leptin levels.

Finally, it was recently demonstrated that although ARC leptin responsiveness is reduced in DIO mice, animals are hyper-responsive to the effects of melanocortin agonists, acting on downstream pathways (Enriori et al. 2007). The presence of an intact melanocortin pathway in situations of leptin resistance is considered an attractive target for pharmacological intervention in obesity (Zhang and Scarpace 2006). However, administration of melanocortin agonists to over-weight humans failed to yield successful results (Hallschmid et al. 2006).

7 Leptin Signalling and Reward Pathways in the Control of Feeding

It is frequently observed that laboratory rodents that have predictable growth curves on a stock pellet diet lose this tight regulatory capability and gain weight and body fat when transferred to a more energy-dense, palatable diet. The development of DIO on diets that are high in fat and simple carbohydrates is often taken as evidence that homeostatic (energy demand-driven) systems are being overridden by non-homeostatic (palatability-, pleasure- or reward-based), hedonic systems, i.e. the interaction between these systems may underlie the tendency to "ignore" feedback repletion signals such as leptin and insulin and over-consume calories when rewarding energy-dense and sweetened foods are available. Some of the historical indicators of interaction between homeostatic and non-homeostatic food intake are reviewed by Figlewicz and Benoit (2009). The mechanisms underlying this interaction remain to be fully resolved although it is clear that there is an extensive motivational circuitry involved in the regulation of food intake within the limbic system of the CNS, in addition to the brainstem and hypothalamic circuits referred to earlier. The motivational circuits encompass parts of the cerebral cortex, hippocampus, and amygdala and the anatomical areas and pathways constituting and running between the ventral tegmental area (VTA) and substantia nigra in the midbrain and the striatum and nucleus accumbens in the forebrain. The dopamine and opioid pathways are major players within this widespread circuitry, and leptin is an external hormonal signal that can influence non-homeostatic behaviours, in addition to its role in energy homeostasis in the hypothalamus (Figlewicz 2003b). Leptin receptors are expressed throughout the limbic forebrain, for example, in dopaminergic neurons in the VTA and substantia nigra, suggesting that these neurons are directly targeted by the leptin hormone (Figlewicz 2003a). What is the effect of leptin on these neurons and on the behaviours they influence? Food restriction enhances the rewarding properties of a variety of stimuli including food, and such states of negative energy balance are accompanied by reduced levels of leptin. Consistent with the idea that low levels of leptin in food restriction increase reward sensitivity (Figlewicz and Benoit 2009), fMRI imaging of individuals with congenital leptin deficiency before and after leptin therapy revealed that the leptin-deficient state was accompanied by activation of striatal areas (Farooqi et al. 2007). The relevance of these observations for more common forms of obesity is provided by the observation that motivation for food rewards is elevated in both food restriction and in obesity accompanied by leptin resistance, where circulating leptin levels are high but signal transduction through the leptin receptor is restricted. Thus, in leptin-resistant obesity, there may be enhanced motivation for rewards, including food reward, thereby stoking the potential to over-consume palatable diets (Pandit etal. 2011).

8 Pharmacological Modification of Leptin Signalling

Shortly after leptin was discovered, the recombinant protein was evaluated for systemic effects in ob/ob, wild-type and db/db mice (Campfield et al. 1995; Halaas et al. 1995; Pelleymounter et al. 1995). The outcomes of these mouse studies established the precedent for the clinical trials that would subsequently be undertaken in humans; recombinant leptin was very active in (naive) ob/ob mice, reduced food intake and body weight, had a more limited effect in wild-type mice where the recombinant protein presumably incrementally augmented endogenous leptin levels, and was ineffective in the receptor-deficient db/db mouse. In humans with congenital leptin deficiency, recombinant leptin is extremely effective (Farooqi et al. 1999), decreases food intake and body weight, and normalises a number of other physiological functions including pubertal development. In contrast, clinical trials in common human obesity have produced disappointing results so far (Heymsfield et al. 1999). Leptin is currently available through an Amylin-sponsored compassionate use programme for treatment of congenital leptin deficiency. More recently, the therapeutic potential of leptin has become recognised in a number of states characterised by a relative hypoleptinaemia, as opposed to complete deficiency, and in particular in lipodystrophy (or lipoatrophy).

Lipodystrophy in humans can be congenital or acquired, for example, through antiretroviral pharmacotherapy of HIV infection. It is characterised by localised or generalised loss of adipose tissue but is accompanied by many of the secondary metabolic symptoms that accompany obesity, such as fatty liver, dyslipidaemia, insulin resistance and type 2 diabetes (Savage and O'Rahilly 2010). The extent of fat loss determines the severity of the metabolic consequences and the degree of leptin deficiency, which in turn drives excessive food consumption. Congenital lipodystrophy is a rare autosomal recessive condition, whereas the acquired condition is common amongst HIV-infected patients (Jacobson et al. 2005). Leptin treatment of congenital lipodystrophy markedly improves metabolic indicators (Oral and Chan 2010), and therapy is effective, albeit less so, in partial lipodystrophy, including that seen with HIV infection (Lee et al. 2006; Mulligan et al. 2009). Leptin is currently available (Amylin expanded access programme) for treating congenital lipodystrophy that presents with associated metabolic symptoms. The sustained improvement observed with leptin therapy in all forms of lipodystrophy—acquired, inherited, generalised or partial (Chong et al. 2010)— has led to calls for wider application to be considered in partial and prediabetic severe lipodystrophy (Savage and O'Rahilly 2010).

Although peripheral leptin monotherapy with leptin or pegylated leptin (Heymsfield et al. 1999; Zelissen et al. 2005) in over-weight or obese hyperlep-tinaemic individuals may not be a realistic intervention for the treatment of obesity due to high endogenous hormone levels and deficiencies in transport into the brain (as discussed above), recent innovation has focused on combination therapy and on developing methods to deliver doses of leptin directly into the CNS, thereby circumventing the issue of BBB passage. A promising alternative to the limited efficacy of monotherapy in hyperleptinaemic obese subjects is combination therapy. One example of this is the co-administration of recombinant leptin (metreleptin) and the amylin analogue, pramlintide. The rationale behind the pramlintide/metreleptin therapy in over-weight and obese patients is the combination of a long-term adiposity signal and a short-term satiety signal. Clinical trials of this combination therapy resulted in greater weight loss (as body fat) than either agent in isolation, a broadly additive effect (Ravussin et al. 2009). Alternative delivery routes to peripheral injection also have potential. In particular, the intra-nasal application of leptin has been an attractive approach (Schulz et al. 2004; Kastin and Pan 2006). Several studies have described in rodents successful uptake of leptin into the brain following intra-nasal delivery, leading to reductions in food intake (Fliedner et al. 2006; Bermudez-Humaran et al. 2007). One previous study reporting on the efficacy of delivering neuropeptides via intra-nasal administration in humans found that alpha-MSH and insulin were both able to induce weight loss in healthy human subjects but not in over-weight individuals (Hallschmid et al. 2004). Thus, it remains to be seen whether these methods might be adapted to present a realistic therapeutic strategy for the treatment of obesity in humans.

Targeting of leptin receptors for the treatment of cancer and cachexia (persistent and potentially harmful weight loss in the presence of a chronic disease, such as cancer) is another expanding field in leptin biology. Although not the focus of this chapter, antagonism of leptin receptors is favourable in the context of some forms of disease, including autoimmune disease, hypertension and tumorigenesis, where leptin plays a stimulatory role in disease progression (Gertler 2006). Severe weight loss, due to reduced appetite and increased sympathetic nervous system activity, is often also experienced in cancer, and in this case, antagonism of LepR is beneficial, bringing about increased appetite and reduced energy expenditure. Several recent reports have developed peptide analogues of leptin that function as selective inhibitors at LepR, and these antagonists have been shown to successfully inhibit cancer cell growth both in vitro and in vivo (Otvos et al. 2010), as well as to increase food intake and weight gain in rodents (Otvos et al. 2010; Shpilman et al. 2011).

9 Conclusions and Future Directions

Since the discovery of leptin, our understanding of the neuroendocrine regulation of feeding and body weight homeostasis has expanded rapidly. Genetic leptin deficiency or mutations impairing leptin receptor signalling within the CNS result in the development of severe obesity. The majority of human obesity, however, is thought to result largely from over-consumption of calories and reduced energy expenditure, lifestyle factors which over time result in progressive increases in body weight. Underlying differences in leptin sensitivity may potentially predispose some individuals to increased susceptibility to obesity in our modern "obesogenic" society. Leptin resistance may also contribute to the over-consumption of highly palatable foods, as reward pathways appear to be enhanced in the absence of leptin signalling.

Pharmacological modulation of leptin receptor signalling has not yet resulted in realistic pharmacological treatments for human obesity, where in most cases hyperleptinaemia and leptin resistance are present. Therapies that are able to circumvent resistance to peripheral leptin treatment, therefore targeting central leptin receptors and overcoming impairments in blood-brain barrier transport, continue to be developed. However, manipulation of leptin receptors may prove useful in the treatment of a range of other diseases, including lipodystrophy and some forms of cancer.


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Supplements For Diabetics

Supplements For Diabetics

All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.

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