Cellular Leptin Signalling System and the Outcome of its deficits
The leptin signalling system begins with the LEPR-B receptor, a type 1 cytokine receptor, that upon leptin binding undergoes a conformation change to activat its associated Jak2 tyrosine kinase. This in turn promotes tyrosine phosphorylation of a number of intracellular residues on LEPR-B, promoting recruitment of downstream molecules tha tlead to intracellular signals. The three distinct tyrosine phosphorylation sites of note in the leptin signalling system are shown in the diagram below. Further genetic and immunohistochemical tsidies are necessary to determine whether these proteins are actually regulated by leptin-responsive neurons, therefore deficits or malfunctinos in the system would be first-order, or they are affected by down-stream circuitries, or alternatively both.
It is however known that dimished leptin action, or “leptin resistance”, is evident in cases of obesity. There are some insights into the mechanisms of this attenuation of LEPR-B signalling, that thus may mediate the leptin resistacne seen in cases of obesity. Within the signalling system itself, as demonstrated in the diagram, there is a negative feedback loop in which LEPR-B Tyr1138-STAT3 singalling promotes transcription and accumulation of SOC3. The binding of SOC3 to Tyr985 then attenuates LEPR-B signalling. Disruption of this process has been shown to decrease food intake and adiposity. Another point of interference in the cellular leptin signalling system is the dephosphorylation of Jak2, which is mediated by protein tyrosine phorphatase, PTP1B. Inactivation of this PTP1B in the brain of mice increases leptin signalling, decreasing adiposity. Peripheral tissue signals also play major role in attenuation of LEPR-B signalling. For example, obesity promotes both enfoplasmic reticulum stress and a state of chronis low-level inflammation that may contribute to attenuation of LEPR-B signalling in obesity. The case of inflammation is however more complex than that of ER stress as some complex forms of inflammation involving the hypothalamus promote anorexia and weight loss. SOC3, PTP1B, ER stress and inflammation thus may represent some of the mediators of the mediators of cellular leptin resistance that is evident in obesity. Whether these mediators themselves are the primary cause of the weight gain/ maintainacne of increased adiposity seen in obesity or are in the most part the effect of the obesity is to date still a mystery, further research is necessary on each individual mechanism and the effects of its deficit in non-obese rodents.
Leptin’s role in energy homeostasis and its relation to obesity
Leptin itself is a cytokine-like hormone produced by adipocytes. It plays a role in regulating energy balance via the central nervous system through its action in activation of the long form of its receptor LEPR-B in the brain to decrease food intake and increase energy expenditure. There is data to suggest that the many distinct roles of leptin, although oberlapping, may be mediated predominantly by different brain nuclei. The phenotypes of both humans and rodents that lack leptin ( Lepob/ob) or LEPR-B ( (Leprdb/db) are morbid obesity, hyperphagia, neuroendocrine dysfunction, and severe hyperglycemia and insulin reistance respectively (which respectively????). Leptin replacement has been shown to reverse this physiology related to low leptin starts indicating therefpre that it is essential for normal energy homeostasis. A role for leptin in regulating peripheral glucose and insulin balance via the central nervous system highlights further its centrality to energy homeostasis. Leptin-deficient Lepob/ob mice have been shown to exhibit profound diabete that can be fully prevented after three-weeks of low dose leptin (Pelleymounter et al 1995). A key area for mediating leptin action on energy homeostasis is the arcuate nucleus of the hypothalamus (ARC). This has been shown by the reduction of food intake simply from injection of leptin directly into the ARC (Satoh et al, 1997) as well as the density of leptin recptor mRNA expressed in th ARC of mice and rats (Elmquist et al 1998). Although this irregulation of energy homeostasis has been highlighted in obese mice, once again a causal effect has not been demonstrated.
Mechanisms in the ARC and their affect on food intake in obesity ???
The arcuate nucleus of the hypothalamus contains two subsets of leptin responsive neurons; anorexigenic POMC neurons and orexigenic agouti-related peptide (AgRP) neurons. POMC neurons release α-melanocyte stimulating hormone (α-MSH) in response to depolarisaiton in response to leptin. α-MSH then mediates anorexigenic effects through activation of melancoritn receptors. AgRP on the other hand is a melanocortin receptor antangonist inhibited by leptin. Its activation leads to a reduction of GRP neuropeptide release, ultimately stimulating feeding. The involvement of these neurons in obesity is evident by the mild obesity found in mice lacking leptin receptors only in POMC or AgRP neurons. Both groups of neurons have therefore been demonstrated to be necessary for maintainance of body weight by leptin (Balthasar et all, 2004). However, as mentioned these mice are only mildly obese, compared to morbidly obese Leprdb/db rats, indicating that other neurons/ mechanisms must play some role in obesity.
Leptin receptors are not solely present on neurons of the ARC but instead are expressed in many other brain nuclei that may play a part in obesity. One such location is the ventro-medial hypothalamic nuclei (VMH), which mediates acute caloric intake suppression, much like the ARC, as well as weight loss. It is also hypothesised that the leptin receptorsof the VMH may have a role in automoic nervous system regulation by leptin (Satoh, 1999). Among others, leptin recetors are also expressed in the ventral tegmental area (VTA), targeting specidifaally the dopamine neurons. This suggests a potential role in brain reward circuitary (Fulton, 2006) and thus may relate greater food intake due to greater reward value of food. (?????) Injection of leptin into the VTA has been shown to reduce food intake. Furthermore, the nucleus tractus solitarius (NTS) provides a major projection zone for sensory nerve inputs from the gastro-intestinal system and contains leptin-regulated neurons (Huo et al, 2006). As leptin injection into this location again also acutely reduces food intake and body weight, it thus appears that the effect of leptin on food intake is mediated by lepin receptos in several nuclei within the hypothalamus, in part via reward-neurons located in the mid-brain, and in part by neurons in the NTS of the caudal brainstem. This suggests that leptin resistance in these areas could play a part in the increased food intake seen in obesity, although future research would need to delve deeper into whether each brain nuclei serce different specific funcitons in regard to control of food intake, or whether they overlap in their mediation of the same behaviour.
Separating cause from effect: Genetic models of obesity
Having discussed already the intricacies of both the cellular leptin signalling cascade and leptins mechanisms of action, as well as their subsequent affects on food intake and energy metabolism leading to obesity, it is important to now focus on their relation to different models of obesity. Although leptin resistance has been shown to have profound effects on mechanism involved in obesity (ie food intake and energy mechanism) and is vital to separate cause and effect.
A great number of genetic mouse models of obesity have been used over the past years. As leptin sensitivity has been shown to be diminished in many obese aninimal models – both diet-induced (DIO) and monogenic and polygenic obesity in rats and mice (but not Lepob/ob ) – “leptin resistance” has in many cases become synonymous with labelling obesity. However the real question is whether deficits in leptin action reflect the underlying initiation of obesity, or a resulting consequence of the obesity itself. Thus, indication of leptin action/abundance in obese animals is of limited value, with far more information coming from animals before weight gain. There is also much variation in the types of genetic deficits found in mice that become obese, thus it is helpful and most necessary to consider many forms of genetic models.
One such model demonstrating cellular leptin resistance in its pruest form would be mutations to LEPR-B itself. Animal models demonstrating these primary mutations have shown that antenuated leptin action is causal to obesity oathogenisis in these animals. Compromising the LEPR-B trafficking or downstream LEPR-B signalling also links causily to obesity. All of these forms of obesity demonstrate a primary causal affect of leptin resistance on obesity.
Alterations in pathways outside the LEPR-B signalling mechanism itself which do however still have affects on leptin action indicate that although the response to leptin may be diminished, leptin may not play a causative role in some facets of genetic obesity. For example, disruption of neural pathways involved in leptin action, like the hypothalamic melanocortin pathway. Although obese animals with deficits in the hypothalamic melanocortin pathway display cellular leptin reistcance and attentuaiton of leptin action, pre-obese animals would have normally functioning cellular LEPR-B signalling and only modest reduction of leptin impact on feeding. The obesity, although leading to attenitaiton of leptin action, is instead primariy caused by the disruption of the melancortin pathway. This same principle can be reiterated in obesity caused by alterations in peripheral tissues.