Obesity is commonly defined as an excessive amount of body fat relative to lean mass.1 Individuals who are classified as obese typically suffer from additional health problems which either do not afflict or have dramatically lower rates of affliction in those who are not obese. Unfortunately in the United States excess weight gain, which commonly leads to obesity, has reached what some are calling epidemic levels with more than 60% of American adults either overweight or obese.1 In addition to the dramatic rise in adult obesity even more concerning is the even more rapid rise in childhood obesity.1
One of the more practical rationalities explaining this dramatic increase in obesity is a change in energy homeostasis between energy intake versus energy expenditure. Energy intake is almost entirely derived from food consumption where energy expenditure is derived from biological thermogenesis which includes basal metabolism, adaptive thermogenesis and physical activity.2 Based on this information it makes sense to argue that an increase in food consumption joined with a corresponding decrease in physical activity due to modern conveniences creates an imbalance resulting in weight gain and obesity.
This explanation can address most of the new increases in adult obesity, but it seems to breakdown when applied to children and infants. Surprisingly, in addition to children and adults, some research demonstrates that even infants have not escaped this obesity epidemic.3 Despite changing food consumption and exercise patterns in adults and young children to teens, little has changed in the diet of infants, either breast milk from mother or bottle formula. One possible explanation is that obese mothers are influencing these changes in their infants, which does have some backing from empirical evidence,3 but at the moment it appears to be a stretch to presume such an explanation to be the principle reason behind this increase.
This change in obesity rate with no definitive explanation stemming from energy intake has lead others to question if the above theory regarding disruption in energy balance is the most influential element behind the obesity rate increase. Make no mistake that an increase in energy imbalance in favor of intake is a significant component in increased obesity rate, but due to the infant ‘question’ it may not be the only significant component. Two other popular explanations have emerged to explain this gap: toxic compounds in the environment and increased viral infections.
These two additional explanations have generated certain levels of empirical backing which add to their legitimacy. However, these elements will not be addressed in this particular blog post, but in a separate post in the future. This blog post will focus on the biochemistry behind how the increasing energy imbalance induces such a significant level of weight gain when under normal circumstances adult body weight is relatively constant despite large variations in daily food intake and energy expenditure.4 Clearly the reaction of the body to hormones and other agents, which govern appetite and energy expenditure change in obese individuals versus non-obese individuals.
Among the hormones that direct energy homeostasis, leptin is widely viewed as one of the most important, if not the most important. Leptin is secreted by adipocytes at a rate which generates serum concentrations in similar proportion to existing adipose tissue.5-7 The principle role of leptin is to provide a measurement of energy to the central nervous system to determine what types of adjustments are required to properly maintain energy homeostasis.8,9 Under normal conditions higher than normal leptin concentrations result in limited to no appetite whereas lower than normal leptin concentrations result in increased appetite as well as reduced energy expenditure and an initialization of the starvation response.10
Most work involving leptin utilize mice as the model organism all which have six distinct leptin receptors (LR) that have been designated a through f and are sub-divided into three classes: short, long and secreted.10 The secreted receptor (LRe) is created via products of alternatively spliced mRNA or proteolytic cleavage of membrane bound LRs.10,11 Secreted forms only contain extracellular domains which bind circulating leptin acting almost like a leptin inhibitor of sorts.10,11 Short receptor (LRa, LRc, LRd and LRf) function is not fully clear, but they are thought to aid leptin transport across the blood brain barrier.11,12 Finally long receptor (LRb) is crucial for leptin action as it is the principle binding receptor, which initiates leptin influence on a given neuron.10
While leptin does act in various portions of the brain, the principle region of action is in the hypothalamus, acting on thyroid and growth hormones along with sex steroids13,14 largely due to high LRb mRNA expression and associated receptor expression.13,15-16 On a side note in addition to appetite, leptin also regulates glucose homeostasis independently of adiposity and regulates glycemia.17-20
The chief area of action for leptin in the hypothalamus is the arcuate nucleus (ARC). In the ARC LRb acts on two different types of neurons: first neuropeptide Y (NPY) and agouti-related peptide (AgRP) synthesizers and second pro-opiomelanocortin (POMC) synthesizers.13,16 For signaling POMC is processed to a-melanocyte-stimulating hormone (aMSH) which binds to melanocortin-3 or 4 receptors (MC3R or MC4R) inducing appetite suppression.21-24 NPY is an orexigenic (promotes food consumption) hormone which incorporates a negative feedback mechanism suppressing growth and reproductive elements as a means to reduce energy expenditure25-27 whereas AgRP is an inverse agonist for MC4R, which also decreases cAMP production.28 Basically both NPY and AgRP act to increase appetite and reduce energy expenditure in times when the body believes a low energy state exists. Leptin binding to LRb inhibits NPY and AgRP secretion16,29 and promotes aMSH secretion in a dose-dependent fashion30 due to promotion of POMC. So overall leptin actively influences appetite by inhibiting appetite promoting NPY and driving POMC synthesis.
When individuals become obese leptin levels do not decrease. In obese individuals leptin levels are actually still represented in somewhat proper proportion to corresponding adipose tissue.7,31-32 The inability of higher leptin concentrations to reduce weight or appetite has lead to the conclusion that obese patients develop some form of leptin resistance.
A vast majority of the studies associated with leptin resistance have taken place in mice, but is also believed to properly translate to humans as well. For the purpose of experimentation mice are commonly divided into a control group and a secondary group that becomes obese due to increased food consumption. This secondary group is commonly referred to as diet-induced obesity (DIO) mice because the obesity is developed through food consumption not genetic knockout or mutation.
In DIO mice the development of leptin resistance has been hypothesized to develop over three stages: first, mice gain weight increasing the amount of adipose tissue and corresponding levels of leptin, but appear to maintain a normal response to leptin. Second, associated leptin interacting peripheral neuronal areas suffer from diminished capacity to respond to leptin. Third, associated leptin interacting central neuronal areas suffer from diminished capacity to respond to leptin.33-35
Evidence for leptin resistance has built considerably over the years. For example between non-obese and DIO mice there are no changes relative to NPY, AgRP and POMC mRNA expression with no leptin exposure.29,36 After leptin is injected decreases NPY and AgRP mRNA expression occur in control mice, but did not change significantly in DIO mice.29 Also DIO mice appear to have less activation of MC4R compared to control mice,29 which makes little sense when considering that DIO mice have higher concentrations of leptin. Some believe that the lack of MC4R activation coupled with no additional reduction in AgRP expression drives leptin resistance downstreatm in the melanocortin system.29
With this information it makes sense to conclude that the leptin resistance is being driven by the leptin concentration itself, not by another element. Studies have appeared to rule out reduced LRb expression as a reason for resistance because LRb mRNA expression typically does not demonstrate a significant difference between control and DIO mice.29,37 While there are many other hypotheses regarding the mechanism of action, the two that receive the most study are the failure of extracellular leptin to reach its appropriate receptors in the brain and the failure of the leptin activated LRb signaling mechanism.38-41
After leptin binds to LRb a number of secondary steps occur. LRb binding initiates the activation of intracellular Jak2 tyrosine kinase. Activation of Jak2 triggers autophosphorylation of the four tyrosine residues on Jak2 as well as phosphorylation of the three tyrosine residues on the intracellular tail of LRb: 985, 1077 and 1138.10 With respect to positive action LRb residue 1138 is the most important as its phosphorylation recruits signal transducer and activator of transcription (STAT) 3, for activation which is directly responsible for transcription of POMC.10 Residue 1077 recruits transcriptional activation of STAT5, which is thought to increase energy expenditure.10
However, to ensure that the effect of leptin does not permeate to a dangerous level, leptin has an inherent negative feedback element. While leptin activation of Jak2 leads to phosphorylation on residue 1138 activating STAT3 leading to the transcription of POMC, STAT3 also results in the transcription of inhibitory suppressor of cytokine signaling 3 (SOCS3).10 SOCS3 acts as the principle negative feedback inhibitor of LRb by binding to residue 985 inhibiting STAT3 recruitment and possibly activation.42,43 Tyrosine phosphatase SHP-2, which is recruited by the phosphorylation of residue 985, is also thought to be a secondary inhibitor, but SOCS3 is considered more important (if not simply based on more confirmed function).42-47 The negative inhibitory ability of SOCS-3 is supported by SOCS-3 deficiencies resulting in significant increased leptin action.29,45 A third LRb inhibitor is tyrosine phosphatase PTP1B, but because this element appears to operate independently of leptin interaction it will not be discussed further.
The rationality behind a feedback mechanism seems straightforward. For obese individuals it may be appropriate that the body limit food consumption and supplement itself through the breakdown adipose tissue, but this process does not supply all necessary nutrients for long-term survival. Therefore, the leptin inhibition feedback mechanism seems designed so that the obese do not overeat, but do eat once and a while in attempt to acquire these essential nutrients. Also the feedback mechanism could be related to necessary changes in behavior which demand greater levels of short-term energy largely derived from food consumption. However, the feedback mechanism may overcompensate in its role in obese individuals.
Relating back to the second theory behind leptin resistance focusing on the activation of the signaling mechanism after the initial binding event, leptin resistance may revolve around an inhibitory desensitization event (similar to nicotinic acetylcholine receptors). For this theory an initial leptin binding event starts the positive secondary mechanism and extended binding begins the inhibitory mechanism. Thus, due to anticipated increases in leptin binding rate and absolute binding times as adipose tissue increases due to an individual becoming obese, leptin response rates at higher leptin concentrations will decrease due to desensitization of LRbs.
Higher baseline SOCS-3 mRNA in the ARC in DIO mice29,48 support the idea of desensitization as if leptin was losing affinity for LRb then SOCS-3 levels would not change significantly. However, what is the cause of this increase? One possibility could be suppose phosphorylation of residue 1138 occurs at a faster rate than phosphorylation of residue 985 (this makes sense if under normal circumstances a sustainable positive effect is seen), but the effect or SOCS-3 has a longer residence time than POMC (recall that POMC is cleaved into aMSH); therefore, the longer leptin stays bound to LRb the more inhibition begins to overtake leptin action. Under this scenario, the longer leptin stays bound to LRb the greater the inhibitory effect on residue 1138 reducing STAT3 activity. Overall the higher concentrations of leptin in obese individuals do not allow for a sufficient period of time for the LRb receptor to “deactivate”, thus leptin action is significantly more inhibited.
Another possibility may be that leptin could bind to the short receptors (LRa, c, d and f), possibly present on the neuron, which could trigger an inhibitory mechanism separate from the initial mechanism associated with LRb. The theory here is that the long receptors have a higher expression rate in neurons which allow for more binding opportunities with leptin, but the short receptors have a higher binding affinity for leptin. As long as there is free leptin the high frequency short-term binding to LRb wins out over the low frequency long-term binding to short LRs, thus leptin represses appetite. However, suppose in situations of high leptin concentrations (obese individuals) more LRe is synthesized and secreted (as a secondary mechanism of inhibition) which binds a lot of the free leptin changing the pattern of influence so that long-term binding short LRs start to have more influence than LRb which leads to leptin resistance. Overall this theory seems more unlikely relative to desensitization as increasing leptin concentrations, no significant reduction in LRb expression and increased SOCS-3 expression all support a form of desensitization and this secondary theory relies on some unknown functionality of certain leptin receptors.
One interesting side note on this element is that STAT3 recruitment decreases profoundly in the ARC, but small recruitment decrease is seen in the ventromedial hypothalamus (VMH) or the dorsomedial hypothalamus (DMH).48 One reason for this suggestion is that cytokine signaling-3 (SOCS-3) expression is also localized to the ARC over other regions49,50 as SOCS-3 reduces the effectiveness of leptin action, probably through inhibition in the secondary pathway. Another reason is that leptin concentration in the VMH or the DMH is not high enough to induce the desensitization element associated with leptin resistance and resulting prolonged decreased STAT3 recruitment. Finally a third possibility may be a more prominent associated helper effect of amylin in the VMH over the ARC.
One of the principle reasons for regionalized increase in SOCS-3 (the first explanation above) could simply be a volume difference due to ARC being localized in a region more conducive to transport of leptin across the blood brain barrier.51 This argument is further supported by a delay in the time course for LRb signaling in non-ARC neurons relative to ARC neurons when exposed to leptin peripherally injected, but this delay does not exist when leptin is centrally injected (central injection skips passage through the blood brain barrier).51
Recall that the concentration of leptin is tied to adipose tissue, thus when exploring the nature of obesity and the role of leptin it is appropriate to investigate the role of saturated fat. Experience with cell culture studies have shown that increasing levels of saturated fat induces increased insulin resistance both in signaling and gene expression due to inhibition of the receptor, receptor substrate 1 and 2 tyrosine phosphorylation and activation of insulin antagonists phosphoinositide-3 (PPI3) kinase and Akt.52-54 There are some conflicting studies regarding how dangerous saturated fat is with regard to catalyzing obesity in different individuals.55,56 A reason behind these opposing results is probably drawn from the complexity of gene response with regards to saturated fat.
For instance one study found that high dietary saturated fat intake significantly increased the risk of obesity by 32% in those carrying 2 or more risk alleles vs. those carrying 0 or 1 risk alleles based on the relationship between STAT3 and saturated fat.52 This study determined that a vast majority of individuals are presumed to have 2 risk alleles making them more susceptible to obesity due to saturated fat consumption.52 The interaction between STAT3 and saturated fat is thought to involve saturated fat activation of toll-like receptor-4 (TLR4) and cross-talk between that activation and the JAK-STAT3 pathway.52,57 This interaction may explain why mice feed diets higher in saturated fat appear to have more aggravated cases of leptin resistance. For example some research demonstrates that for diets equally high in total fat the one comprised predominately of poly-unsaturated fat does not significantly change NPY or AgRP mRNA levels in the ARC unlike diets comprised predominately of poly-saturated fat.58 Based on this result leptin levels should be inhibited less for unsaturated fat as opposed to saturated fat.
However, an unexpected side result is that POMC mRNA expression does not change regardless of principle fat component of the diet.58 This result is unexpected because with more leptin resistance there should be some corresponding drop in POMC mRNA expression. One explanation for this result could be that there was a decrease, but the decrease was not observed because the time frame of the experiment was not long enough. Overall ARC-based NPY and AgRP also seem tied to saturated fat content largely stemming from the increases in leptin concentration derived from saturated fat instead of just total fat content.
Another issue regarding leptin resistance involves how it influences overall appetite. For the purpose of this discussion take two individuals one who is not obese and one who is obese. The overall influence of leptin resistance can be viewed in two ways. First, when an individual moves from not obese to obese leptin loses effectiveness, but not in a negative fashion; the overall leptin effect is higher than that seen in the non-obese individual, but the leptin influence ratio decreases. For example a non-obese individual with 100 ug of leptin would eat 900 calories instead of 1000 calories whereas an obese individual with 200 ug of leptin would eat 850 calories instead of 1000 calories. Second, when an individual moves from not obese to obese leptin effectiveness becomes negative both overall and as a ratio. In this scenario an individual with 200 ug of leptin would eat 930 calories. The second scenario seems supported by conclusions that food intake is increased in obese individuals ranging from 14 to 17%58 as well as decreased STAT3 phosphorylation and other LRb signaling.10 Thus if this result accurately depicts the second scenario leptin resistance must be fairly significant, creating a positive feedback loop expanding the probability that an individual remains obese.
One question from this second scenario is that even while food intake increases in obese individuals, in the short-term NPY and AgRP mRNA (and protein) levels drop.58 There does not appear to be any significant information pertaining to whether or not these mRNA levels rebound in the presence of long-term leptin resistance. If the NPY/AgRP values do rebound then it would be significant evidence that leptin was the defining element connecting NPY/AgRP and saturated fat. If not, then there most likely needs to be a secondary element which links NPY/AgRP decrease and saturated fat apart from leptin. If this is the case the most promising element for this secondary linkage is STAT3 and its TLR4 saturated fat link.
Recent information has determined that leptin may not only regulate appetite, but may also interact with dopamine neurons stimulating the reward pathway in the brain.59-62 Leptin is now thought to act in consort with the mesolimbic dopamine system which is made up of dopamine releasing neurons in the ventral tegmental area (VTA) which innervate into the striatum, amygdala and prefrontal cortex.59 In addition to some neurons expressing LRb in the VTA, other studies have identified LRb expressing neurons in the lateral hypothalamic area (LHA) which project to the VTA.10 Therefore, it appears that there are two separate leptin based systems which could influence the dopamine based reward pathway in some context. This effect would especially be prominent if leptin limited the pleasure received from consuming food because then the development of leptin resistance would neutralize this limiting characteristic increasing the probability of greater food consumption in obese individuals.
With regards to leptin resistance and its overall influence on obesity it may have an important partner in amylin. Amylin is a 37 amino acid peptide hormone commonly co-secreted with insulin from pancreatic b-cells,64 which principally binds to receptors in the hindbrain area postrema (AP).65,66 The importance of amylin relative to leptin and obesity is a number of experiments have demonstrated that increasing concentrations of amylin in both non-obese and obese individuals induces weight loss with an increased reduction when combined with leptin.66,67 One lingering question is whether or not this weight loss can be principally attributed to amylin directly or if amylin reduces leptin resistance allowing leptin to be more effective.
One piece of evidence which supports the latter explanation and ties to the issue of leptin resistance is that amylin-augmented weight loss in DIO rats was observed with an increase in POMC expression in the ARC.68,69 This increase in POMC expression implies that weight loss seen in obese individuals due to increased levels of amylin would eventually be realized as reduced food intake due to aMSH binding, an increase probably stemming from leptin derived POMC increases.
While leptin activity in the ARC is important it appears, not surprisingly, that it not the exclusive operating area for leptin influence with regards to appetite control. Selective lesioning of leptin receptors on ARC POMC neurons does not completely replicate the development of obesity which accompanies general leptin deficiency (from knockouts).48 Also leptin resistance demonstrates a decrease in STAT3 signaling throughout the VMH and AP which support the notion of leptin resistance beyond the ARC.70,71 Therefore, the mechanism behind amylin induced reduction of leptin resistance could stem from amylin increasing signal effectiveness in the VMH and AP.66
Action in the VMH is supported by an approximate 43% increase in leptin signaling (derived from STAT3 comparisons) in the VMH without any direct increase in the ARC.66,72 An increase in STAT3 concentration coincides with other studies.67 The important targets for leptin in the VMH appear to be glucose-sensitive neurons and transcription factor SF-1.73-76 Transcription factor SF-1 could be important because it induces DIO in mice that lack it.77 One reason explaining this result is that co-localization studies identify SF-1 VMH neurons linked to leptin-induced activation of STAT3.66
No changes in leptin response were seen in the caudal nucleus of the solitary tract (NTS) with direct amylin treatment.66 Nor did amylin influence leptin, LRb or SOCS-3 concentrations via gene expression changes.66 Once again the lack of amylin influence on leptin, LRb, SOCS-3 could be a timecourse issue due to measurements not being long enough or taken at the appropriate time, but overall this is unlikely. Moreover it is unlikely that the AP is a site of cooperative action between leptin and amylin due to the low level of overall expression of leptin receptors and low leptin-derived STAT3 expression.66,78 Also amylin receptors are limited in the ARC and amylin administration does not activate c-Fos in the hypothalamus.79,80 Finally amylin functions through calcitonin receptor binding using receptor activity-modulating protein (RAMP) via a second messenger cGMP81,82 not through Jak kinases lke leptin. Therefore, if the principle area of action for amylin is the AP its action must propogate from the AP to an area more conducive for leptin action like the VMH.
Based on all of the results amylin influence seems to be localized to its respective receptors in the AP and through neuronal connections (probably polysynaptic) act upstream on the VMH enhancing leptin response through the NTS and the lateral parabrachial nucleus (lPBN).66,79,84,85 This conclusion is supported by amylin binding in the AP activating the NTS, IPBN and central nucleus in the amygdala to inhibit fasting derived activation of the lateral hypothalamic (LH) area65 where LH afferents are thought to influence VMH signaling.86,87 Also lesions on the lPBN blocked amylin-induced c-Fos expression.83 There is also some evidence to suggest that leptin binding is also increased in the DMN.66 In addition leptin may have a feedback effect on amylin in that amylin effectiveness is reduced in LRb knockouts.88
So how does amylin binding aid leptin? Amylin knockout mice exhibited overall reduced leptin signaling in response to exogenous leptin, largely patterned with a reduced residence time of action.66 This reduction in operational time (initially the leptin was able to function and later become less effective) is thought to involve a reduction in LRb expression.66 A smaller amount of LRb would result in faster desensitization of available receptors and loss of leptin activity.
The reverse of this thought process makes sense to why amylin may ‘rescue’ leptin action in obese individuals. Recall that STAT3 expression does not appear significantly reduced in non-ARC areas of leptin action like the VMH (this is probably the reason that most obese individuals do not incessantly eat). Increased amylin concentrations could increase the amount of LRb expression creating more leptin binding targets. More leptin binding targets would reduce the overall binding time a given LRb had with leptin generating more ‘deactivation’ time which could reduce the rate of desensitization. This theory is further supported by other data demonstrating a 70% increase in ARC leptin binding with amylin/leptin sustained infusion.67 However, there is little information regarding how long-term the weight loss produced by amylin augmentation may be. Overall it is difficult to conclude that amylin by itself can result in enough weight loss to reduce leptin concentration enough to eliminate leptin resistance in combination with greater LRb expression.
Overall leptin and amylin appear to have cooperative effect in managing energy intake and expenditure in humans. While leptin appears to have a greater overall influence, especially in non-obese individuals due to a lack of resistance, both molecules are able to reduce weight in non-obese and obese individuals individually, but their effects are significantly augmented when both are present. Like leptin, amlyin is also thought to increase energy expenditure.69,89,90 The nature of leptin resistance and the general decrease in weight in response to increased amylin levels due to injection or other means of administration leads to two conclusions. First, it seems reasonable to suggest that amylin concentrations in obese individuals could also be negatively affected either in a manner of overall availability or its overall effectiveness (similar to leptin). Second, amylin as an outside therapeutic target (endogenous administration) does not appear to have the necessary influence for use as a stand-alone treatment for obesity because while weight is lost, the overall obesity does not appear reversed.
Ghrelin is another element which may play a meaningful role in energy regulation affecting the probability of becoming obese. The principle role of ghrelin is to stimulate growth hormone release91-93 it is also thought to play a role in regulation of body weight.94,95 Its role in regulation comes from the response of increasing ghrelin concentrations stimulating appetite with a corresponding decrease in levels after eating, more than likely induced by insulin and leptin.96-99 Ghrelin exerts its effect by binding to NPY/AgRP neurons. The reason behind this appetite stimulation aspect of ghrelin could stem from its relationship with growth hormones as more available energy is typically advantageous to augmenting the effectiveness of growth hormones.
A vast majority of synthesized ghrelin is produced in the stomach so to act in the brain it needs to cross the blood brain barrier, similar to leptin. Studies have shown that due to the non-saturated, saturated transport structure used by ghrelin normal individuals typically have an inverse relationship between weight and ghrelin transport.100 Unlike what is believed for leptin, not surprising given the general opposition of their roles, triglycerides promote ghrelin transport across the blood brain barrier rather than inhibit.100 The ghrelin promotion effect makes sense if one believes that triglycerides are a signal to the brain for starvation.101 However, the loss of transport in obese mice is not accounted for by triglycerides leading others to conclude that there must be a second secreted molecule which drives this transport inefficiency. One possibility may be obestatin.
From a synthesis standpoint leptin inhibition of ghrelin seems to make sense both in the opposing effects on appetite as well as obese individuals having lower baseline concentrations of ghrelin than non-obese individuals.102,103 However, the interesting element to this lower baseline is that it does not appear to be uniform (steady-state). Instead the relationship between ghrelin concentrations in obese and non-obese individuals differed based on time of day with daylight levels being somewhat similar with obese individuals having much lower concentrations at night.94
Currently the reason behind the significant change in ghrelin concentration at night is unknown, but a consequence of this change may relate to obesity from a standpoint of energy expenditure more than energy intake. Despite significant increases in ghrelin concentration during the night in healthy individuals, there is little food consumption or need for food consumption to correspond to this increase; therefore, these concentration increases probably have more to do with growth hormone regulation than energy intake. Growth hormone activation typically results in greater energy expenditure. However, in obese individuals if nocturnal ghrelin concentrations are not increasing then there is less growth hormone activity which can result in stunted growth, less efficient cell repair and less overall energy consumption. Thus this change in ghrelin concentration could be another positive feedback associated with obesity in that the more obese an individual is the less energy he/she expends during the night through the use of growth hormones, thus increasing the probability of maintaining that obesity.
One final issue is that there is some question whether or not leptin transport across the blood-brain barrier is obstructed in obese individuals compared to non-obese individuals. If leptin transport activity is negatively influenced it could offer an alternative explanation to why greater concentrations of leptin may induce less leptin activity. Unfortunately there are two immediate problems with this theory. First, the methodology explaining how obesity negatively influences leptin transport is unknown and little viable explanations exist to why obesity would negatively affect transport. The best explanation could be that triglycerides, which typically increase in concentration as an individual becomes more obese, reduce leptin transport, but the demanded volume of reduction seems too high from an intuitive standpoint. Second, decreases in leptin transport are counter to the demonstrated increases in SOCS-3 concentrations in DIO mice. Therefore, even if leptin transport across the blood-brain barrier is reduced in obese individuals, which is still questionable,71,104-106 it is difficult to suggest that this reduction is significant enough to act as a meaningful explanation for ‘leptin resistance’.
Overall the process of moving from a non-obese individual to an obese individual from an energy balance perspective appears to lean heavily on hormone leptin. Leptin functions not only to influence appetite, but also reward pathways inducing a secondary biochemical means to affect food consumption and a possible interaction with saturated fat which may change leptin secretion patterns. The biggest energy balance element driving maintenance of obesity is the development of leptin resistance which probably follows a desensitization pathway with leptin saturation relative to LRb in the ARC. In addition to leptin, amylin and ghrelin also play important roles in appetite regulation and energy expenditure.
At the moment there does not appear to be a ‘silver’ bullet treatment for obesity on a biochemical level. However, there are opportunities for co-therapies to be successful. For example as previously mentioned it does not appear that increasing amylin concentration will be sufficient to overcome leptin resistance in obese individuals; however, co-therapy using an amylin mimic and an aMSH agnoist could work together to overcome a significant potion of the leptin resistance. Further study of obestatin could lead to a better understanding of its role, if any, in ghrelin function and whether or not it would be useful in treatment. Another option may be cholecystokinin which has shown to indirectly increase STAT3 concentration in low-dose leptin environments.107 Finally there is the lingering option of addressing SOCS-3 concentration changes through inhibition. Therefore, while addressing obesity appears to be a difficult mountain to climb, by better understanding the biochemical realities and changes between obese individuals and non-obese individuals both new drug therapies and food consumption strategies can be developed to combat obesity in a safe, cost-effective and appropriate manner.
1. Zamboni, M, et, Al. “Health consequences of obesity in the elderly: a review of four unresolved questions.” Int. J. Obes. (Lond.) 2005. 29: 1011–1029.
2. Enriori, P, et, Al. “Leptin Resistance and Obesity.” Obesity. 2006. 14: 254S-258S.
3. Whitaker, R. “Predicting Preschooler Obesity at Birth: The Role of Maternal Obesity in Early Pregnancy.” Pediatrics. 2004. 114:29-36.
4. Seeley, R.J, and Woods, S. “Monitoring of stored and available fuel by the CNS: implications for obesity.” Nat. Rev. Neurosci. 2003. 4:
5. Zhang, Y, et, Al. “Positional cloning of the mouse obese gene and its human homologue.” Nature. 1994. 372:425–32.
6. Maffei, M, et, Al. “Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects.” Nat Med. 1995. 1:1155–61.
7. Considine, R, et, Al. “Serum immunoreactive-leptin concentrations in normal-weight and obese humans.” N Engl J. Med. 1996. 334:292–5.
8. de Luca, C, et, Al. “Complete rescue of obesity, diabetes, and infertility in db/db mice by neuronspecific LEPR-B transgenes.” J. Clin. Invest. 2005. 115: 3484–3493.
9. Spiegelman, B and Flier, J. “Obesity and the regulation of energy balance.” Cell. 2001. 104:531– 43.
10. Myers, M, Cowley, M, Munzberg, H. “Mechanisms of Leptin Action and Leptin Resistance.” Annu. Rev. Physiol. 2008. 70:537-556.
11. Ge, H, et, Al. “Generation of soluble leptin receptor by ectodomain shedding of membrane-spanning receptors in vitro and in vivo.” J. Biol. Chem. 2002. 277:45898–903.
12. Uotani, S, et, Al. “Functional properties of leptin receptor isoforms: internalization and degradation of leptin and ligand-induced receptor downregulation.” Diabetes. 1999. 48:279–86.
13. Elmquist, J, Elias, C, Saper, C. “From lesions to leptin: hypothalamic control of food intake and body weight.” Neuron. 1999. 22:221–32.
14. Inui, A. “Feeding and body-weight regulation by hypothalamic neuropeptides—mediation of the actions of leptin.” Trends Neurosci. 1999. 22:62–67.
15. Baskin, D, et, Al. “Leptin receptor long-form splice-variant protein expression in neuron cell bodies of the brain and colocalization with neuropeptide Y mRNA in the arcuate nucleus.” J. Histochem. Cytochem. 1999. 47:353–62.
16. Schwartz, M, et, Al. “Central nervous system control of food intake.” Nature. 2000. 404:661–71.
17. Liu, L, et, Al. “Intracerebroventricular leptin regulates hepatic but not peripheral glucose fluxes.” J. Biol. Chem. 1998. 273:31160–67.
18. Burcelin, R, et, Al. “Acute intravenuous leptin infusion increases glucose turnover but not skeletal muscle glucose uptake in ob/ob mice.” Diabetes. 1999. 48:1264–69.
19. Kieffer, T, et, Al. “Leptin suppression of insulin secretion by the activation of ATP-sensitive K+ channels in pancreatic beta-cells.” Diabetes. 1997. 46:1087–93.
20. Covey, S, et, Al. “The pancreatic beta cell is a key site for mediating the effects of leptin on glucose homeostasis.” Cell Metab. 2006. 4:291–302.
21. Huszar, D, et, Al. “Targeted disruption of the melanocortin-4 receptor results in obesity in mice.” Cell. 1997. 88:131–41.
22. Butler, A, and Cone, R. “The melanocortin receptors: lessons from knockout models.” Neuropeptides. 2002. 36:77–84.
23. Ste, M, et, Al. “A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors.” PNAS. 2000. 97:12339–44.
24. Chen, A, et, Al. “Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass.” Nat. Genet. 2000. 26:97–102.
25. Erickson, J, Hollopeter, G, Palmiter, R. “Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y.” Science. 1996. 274:1704–1707.
26. Clark, J, Kalra, P, Kalra, S. “Neuropeptide Y stimulates feeding but inhibits sexual behavior in rats.” Endocrinology. 1985. 117:2435–42.
27. Smith, M, and Grove, K. “Integration of the regulation of reproductive function and energy balance: lactation as a model.” Front. Neuroendocrinol. 2002. 23:225–56.
28. Ollmann, M, et, Al. “Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein.” Science. 1997. 278:135–38.
29. Enriori, P, et, Al. “Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons.” Cell Metab. 2007. 5:181–94.
30. Li, J, et, Al. “Agouti-related protein-like immunoreactivity: characterization of release from hypothalamic tissue and presence in serum.” Endocrinology. 2000. 141: 1942–1950.
31. Farooqi, I, and O’Rahilly, S. “Monogenic obesity in humans.” Annu. Rev. Med. 2005. 56:443–458.
32. Maffei, M, et, Al. “Absence of mutations in the human Ob gene in obese/diabetic subjects.” Diabetes. 1996. 45:679–82.
33. El-Haschimi, et, Al. “Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity.” J Clin Invest. 2000. 105:1827–32.
34. Lin, S, et, Al. “Development of high fat diet-induced obesity and leptin resistance in C57Bl/6J mice.” Int J Obes Relat Metab Disord. 2000. 24:639–46.
35. Prpic, V, et, Al. “Differential mechanisms and development of leptin resistance in A/J versus C57BL/6J mice during dietinduced obesity.” Endocrinology. 2003. 144:1155– 63.
36. Takahashi, N, et, Al. “Divergent effects of leptin in mice susceptible or resistant to obesity.” Horm. Metab. Res. 2002. 34: 691–697.
37. Sahu, A, Nguyen, L, O’Doherty, R. “Nutritional regulation of hypothalamic leptin receptor gene expression is defective in diet-induced obesity.” J. Neuroendocrinol. 2002. 14: 887–893.
38. Banks, W, and Farrell, C. “Impaired transport of leptin across the blood-brain barrier in obesity is acquired and reversible.” Am J Physiol Endocrinol Metab. 2003. 285:E10 –5.
39. Munzberg, H, and Myers, M. Jr. “Molecular and anatomical determinants of central leptin resistance.” Nat Neurosci. 2005. 8:566–70.
40. Banks, W. “The many lives of leptin.” Peptides. 2004. 25:331–38.
41. Bouret, S, and Simerly, R. “Developmental programming of hypothalamic feeding circuits.” Clin. Genet. 2006. 70:295–301.
42. Bjørbæk, C, et, Al. “SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985.” J. Biol. Chem. 2000. 275:40649–57.
43. Bjørbæk C, et, Al. “Identification of SOCS-3 as a potential mediator of central leptin resistance.” Mol. Cell. 1998. 1:619–25.
44. Dunn SL, Bjornholm M, Bates SH, Chen Z, Seifert M, Myers MG Jr. 2005. Feedback
inhibition of leptin receptor/Jak2 signaling via Tyr1138 of the leptin receptor and
suppressor of cytokine signaling 3. Mol. Endocrinol. 19:925–38
45. Mori, H, et, Al. “Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity.” Nat. Med. 2004. 10:739–43.
46. Howard, J, et, Al. “Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3.” Nat. Med. 2004. 10:734–38.
47. Zhang, E, et, Al. “Neuronal Shp2 tyrosine phosphatase controls energy balance and metabolism. PNAS. 2004. 101:16064–69.
48. Munzberg, H, Flier, J, and Bjorbaek, C. “Region-specific leptin resistance within the hypothalamus of diet-induced obese mice.” Endocrinology. 2004. 145:4880–4889.
49. Tups, A, et, Al. “Photoperiodic regulation of leptin sensitivity in the Siberian hamster, Phodopus sungorus, is reflected in arcuate nucleus SOCS-3 (suppressor of cytokine signaling) gene expression.” Endocrinology. 2004. 145:1185–93.
50. Krol, E, et, Al. “Altered expression of SOCS3 in the hypothalamic arcuate nucleus during seasonal body mass changes in the field vole, Microtus agrestis.” J. Neuroendocrinol. 2007. 19:83–94.
51. Faouzi, M, et, Al. “Differential accessibility of circulating leptin to individual hypothalamic sites.” Endocrinology. 2007. 148:5414–23.
52. Phillips, C, et, Al. “Dietary Saturated Fat Modulates the Association between STAT3 Polymorphisms and Abdominal Obesity in Adults.” J. Nutr. 2009. 139: 2011–2017.
53. Frangioudakis, G, Ye, J, Cooney, G. “Both saturated and n-6 polyunsaturated fat diets reduce phosphorylation of insulin receptor substrate-1 and protein kinase B in muscle during the initial stages of in vivo insulin stimulation.” Endocrinology. 2005. 146:5596–603.
54. Ruddock, M, et, Al. “Saturated fatty acids inhibit hepatic insulin action by modulating insulin receptor expression and post-receptor signalling.” J. Biochem. 2008. 144:599–607.
55. Brunner, E, Wunsch, H, Marmot, M. “What is an optimal diet? Relationship of macronutrient intake to obesity, glucose tolerance, lipoprotein cholesterol levels and the metabolic syndrome in the Whitehall II study.” Int J Obes Relat Metab Disord. 2001. 25:45–53.
56. Doucet, E, et, Al. “Dietary fat composition and human adiposity.” Eur J Clin Nutr. 1998. 52:2–6.
57. Hu, X, et, Al. “Crosstalk among Jak-STAT, Tolllike receptor, and ITAM-dependent pathways in macrophage activation.” J. Leukoc Biol. 2007. 82:237–43.
58. Wang, H, Storlien, L, and Huang, X. “Effects of dietary fat types on body fatness, leptin, and ARC leptin receptor, NPY, and AgRP mRNA expression.” Am J Physiol Endocrinol Metab. 2002. 282:E1352-E1359.
59. Figlewicz, D, et, Al. “Intraventricular insulin and leptin reverse place preference conditioned with high-fat diet in rats.” Behav. Neurosci. 2004. 118:479–87.
60. Figlewicz, D, and Woods, S. “Adiposity signals and brain reward mechanisms.” Trends Pharmacol. Sci. 2000. 21:235–36.
61. Carr, K. “Chronic food restriction: enhancing effects on drug reward and striatal cell signaling.” Physiol. Behav. 2007. 91:459–72.
62. Shizgal, P, Fulton, S, Woodside, B. “Brain reward circuitry and the regulation of energy balance.” Int. J. Obes. Relat. Metab. Disord. 2001 25(Suppl. 5):S17–21
63. Kelley, A, and Berridge, K. “The neuroscience of natural rewards: relevance to addictive drugs.” J. Neurosci. 2002. 22:3306–11.
64. Ogawa, A, et, Al. “Amylin secretion from the rat pancreas and its selective loss after streptozotocin treatment.” J Clin Invest. 1990. 85:973–976.
65. Lutz, T. “Amylinergic control of food intake.” Physiol Behav. 2006. 89:465–471.
66. Roth, J, et, Al. “Leptin responsiveness restored by amylin agonism in diet-induced obesity: Evidence from nonclinical and clinical studies.” PNAS. 2008. 105(20): 7257-7262.
67. Turek, V, et, Al. “Mechanisms of Amylin/Leptin Synergy in Rodent Models.” Endocrinology. 2010. 151:143–152.
68. Roth, J, et, Al. “Antiobesity effects of the β-cell hormone amylin in diet-induced obese rats: Effects on food intake, body weight, composition, energy expenditure, and gene expression.” Endocrinology. 2006. 147:5855–5864.
69. Mack, C, et, Al. “Pharmacological actions of the peptide hormone amylin in the long-term regulation of food intake, food preference and body weight.” Am J Physiol. 2007. 293:R1855–R1863.
70. Balthasar N, et, Al. “Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis.” Neuron. 2004. 4:983–991.
71. Levin, B, Dunn-Meynell, A, Banks, WA. “Obesity-prone rats have normal blood–brain barrier transport but defective central leptin signaling before obesity onset.” Am J Physiol. 2004. 286:R143–R150.
72. Patterson, C, et, Al. “Three weeks of postweaning exercise in DIO rats produces prolonged increases in central leptin sensitivity and signaling.” AmJ Physiol Regul Integr Comp Physiol. 2009. 296:R537–R548.
73. Dhillon, H, et, Al. “Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis.” Neuron. 2006. 49:191–203.
74. Jacob, R, et, Al. “The effect of leptin is enhanced by microinjection into the ventromedial hypothalamus.” Diabetes. 1997. 46:150–152.
75. Elmquist, J, et, Al. “Leptin activates distinct projections from the dorsomedial and ventromedial hypothalamic nuclei.” PNAS. 1998. 95:741–746.
76. Canabal, D, et, Al. “Glucose, insulin and leptin signaling pathways modulate nitric oxide (NO) synthesis in glucose-inhibited (GI) neurons in the ventromedial hypothalamus (VMH).” Am J Physiol. 2007. 292:R1418–R1428.
77. Majdic, G, et, Al. “Knockout mice lacking steroidogenic factor 1 are a novel genetic model of hypothalamic obesity.” Endocrinology. 2002. 143:607–614.
78. Elmquist, J, et, Al. “Distributions of leptin receptorm RNA isoforms in the rat brain.” J. Comp Neurol. 1998. 395:535–547.
79. Riediger, T, et, Al. “The anorectic hormone amylin contributes to feeding-related changes of neuronal activity in key structures of the gut-brain axis.” Am J Physiol Regul Integr Comp Physiol. 2004. 286:R114–R122.
80. Rowland, N, Crews, E, Gentry, R. “Comparison of Fos induced in rat brain by GLP-1 and amylin.” Regul Pept. 1997. 71:171–174.
81. Christopoulos, G, et, Al. “Multiple amylin receptors arise from receptor activity-modifying protein interaction with the calcitonin receptor gene product.” Mol Pharmacol. 1999. 56:235–242.
82. Riediger, T, et, Al. “Amylin potently activatesAPneurons possibly via formation of the excitatory second messenger cGMP.” Am J Physiol Regul Integr Comp Physiol. 2001. 281:R1833–R1843.
83. Lutz, T. “Roles of Amylin in Satiation, Adiposity and Brain Development.” Forum Nutr. Basel, Karger. 2010. 63:64-74.
84. Becskei, C, et, Al. “Lesion of the lateral parabrachial nucleus attenuates the anorectic effect of peripheral amylin and CCK.” Brain Res. 2007. 1162:76–84.
85. Rowland, N, and Richmond, R. “Area postrema and the anorectic actions of dexfenfluramine and amylin.” Brain Res. 1999. 820:86–91.
86. Fahrbach, S, Morrell, J, Pfaff, D. “Studies of ventromedial hypothalamic afferents in the rat using three methods of HRP application.” Exp Brain Res. 1989. 77:221–233.
87. Ono, T, et, Al. “Topographic organization of projections from the amygdala to the hypothalamus of the rat.” Neurosci Res. 1985. 2:221–238.
88. Eiden, S, et, Al. “Salmon calcitonin: a potent inhibitor of food intake in states of impaired leptin signalling in laboratory rodents.” J. Physiol. 2002. 541:1041–1048.
89. Osaka, T, et, Al. “Central and peripheral administration of amylin induces energy expenditure in anesthetized rats.” Peptides. 2008. 29:1028–1035.
90. Isaksson, B, et, Al. “Chronically administered islet amyloid polypeptide in rats serves as an adiposity inhibitor and regulates energy homeostasis.” Pancretology. 2005. 5:29–36.
91. Kojima, M, et, Al. “Ghrelin is a growth-hormone-releasing acylated peptide from stomach.” Nature. 1999. 402(6762):656-60.
92. Takaya, K, et, Al. “Ghrelin strongly stimulates growth hormone release in humans.” J. Clin. Endocrinol. Metab. 2000. 85(12):4908-11.
93. Peino, R, et, Al. “Ghrelin-induced growth hormone secretion in humans.” Eur. J. Endocrinol. 2000. 143(6):R11-4.
94. Yildiz, B, et, Al. “Alterations in the dynamics of circulating ghrelin, adiponectin, and leptin in human obesity.” PNAS. 2004. 101(28):10434-10439.
95. Wren, A, et, Al. “Ghrelin enhances appetite and increases food intake in humans.” J. Clin. Endocrinol. Metab. 2001. 86(12):5992.
96. Cummings, D, et, Al. “A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans.” Diabetes. 2001. 50(8):1714-9.
97. Tschop, M, et, Al. “Post-prandial decrease of circulating human ghrelin levels.” J. Endocrinol Invest. 2001. 24(6):RC19-21.
98. Anderwald, C, et, Al. “Insulin-dependent modulation of plasma ghrelin and leptin concentrations is less pronounced in type 2 diabetic patients.” Diabetes. 2003. 52(7):1792-8.
99. Barazzoni, R, et, Al. “Hyperleptinemia prevents increased plasma ghrelin concentration during short-term moderate caloric restriction in rats.” Gastroenterology. 2003. 124(5):1188-92.
100. Banks, W, Burney, B, Robinson, S. “Effects of Triglycerides, Obesity, and Starvation on Ghrelin Transport Across the Blood-Brain Barrier.” Peptides. 2008. 29(11): 2061–2065.
101. Banks, W, Farr, S, Morley, J. “The effects of high fat diets on blood-brain barrier transport of leptin: Failure or Adaptation?” Physiol Behav. 2006. 88:244–248.
102. Zigman, J, and Elmquist, J. “Minireview: From anorexia to obesity--the yin and yang of body weight control.” Endocrinology. 2003. 144(9):3749-56.
103. Shiiya, T, et, Al. “Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion.” J. Clin. Endocrinol. Metab. 2002. 87(1):240-4.
104. Adam, C, Findlay, P. “Decreased blood–brain leptin transfer in an ovine model of obesity and weight loss: resolving the cause of leptin resistance.” International Journal of Obesity. 2010. 34:980–988.
105. Rahmouni, K, et, Al. “Leptin resistance contributes to obesity and hypertension in mouse models of Bardet-Biedl syndrome.” J Clin Invest. 2008.118(4):1458–1467.
106. Burguera, B, et, Al. “Obesity Is Associated With a Decreased Leptin Transport Across the Blood-Brain Barrier in Rats” Diabetes. 2000. 1219-1223.
107. Merino, B, et, Al. “Leptin mediated hypothalamic pathway of cholecystokinin (CCK-8) to regulate body weight in free-feeding rats.” Endocrinology. 2008. 149:1994 –2000.”