Therapeutic Implications
Leptin deficiency produces dramatic pathology, while hyper-Leptinaemia is less dramatic clinically. This might suggest the predominant role of Leptin in maintaining food intake or preservation of a minimum optimal body weight, rather than as a weight regultor which could facilitate weight loss in the growingly obese animal. Although initially thought of as an anti-obesity hormone, Leptin's primary role seems to be metabolic signaling to the brain from the adipocytes regarding energy sufficiency rather than excess, conferring a survival advantage in times of negative energy balance. In today's developed world this survival advantage is needed less and less due to abundance of food sources. Thus Leptin probably does not play a direct role to facilitate energy loss in times of energy excess. Despite this, achieving supraphysiological levels of Leptin remains a lucrative concept to treat obesity. Unfortunately Leptin administration studies with subcutaneous infusions have shown variable results. 54 lean and 73 obese subjects were treated with Leptin at different doses for 24 weeks. JAMA. 1999 Oct 27;282(16):1568-75. The placebo group lost 1.3 kg , while the Leptin group with the higher dosing lost 7.1 kg, 95% of the weight loss being due to fat mass loss. Overall, the weight loss was not impressive, but clearly a subgroup of patients did respond to Leptin, and elucidation of their characteristics might hold promise for the future of Leptin therapy. Long term safety, tolerance, and efficacy of Leptin administration in humans remains to be studied. The advantages of combining Leptin therapy with other presently available anti-obesity drugs need to be assessed. The effects and side-effects on other systems with Leptin administration would be determining factors in Leptin's evolution as an anti-obesity drug. Lipodystrophic patients may be another group of patients who might benefit from leptin treatment in the long term as has been demonstrated in early studies lasting for up to 12 months. Diabetes. 2005 Jul;54(7):1994-2002.
Trying to overcome Leptin resistance with higher doses of Leptin seems a straightforward option. But if it is to be successfully accomplished, the factors producing Leptin resistance will have to be better elucidated. To understand the factors contributing to Leptin resistance a brief understanding of the mechanism of Leptin signalling is crucial. Leptin acts through the long form of its receptor LROb. LROb does not have intrinsic enzymatic activity, but it signals through three distinct pathways- J Biol Chem. 2000 May 12;275(19):14563-72 firstly through autophosphorylation of its Tyr985 residue, secondly through autophosphorylation of the Tyr1138 residue, and thirdly through activation of Jak2 (JAK family of tyrosine Kinase). Trends Genet. 1995 Feb;11(2):69-74. Phosphorylation of the Tyr1138 residue of LROb results in recruitment of the latent transcription factor STAT3 to the LROb-Jak2 complex with tyrosine phosphorylation and nuclear translocation of STAT3. STAT3 then activates not only the transcription of POMC, but also that of SOCS3 (Suppressor of Cytokine signalling). The SOCS3 then binds to Tyr985 of LROb producing inhibition of the above mentioned LROb>STAT3 signalling, J Biol Chem. 1999 Oct 15;274(42):30059-65 thus producing inhibition of further Leptin signalling. Mol Endocrinol. 2005 Apr;19(4):925-38. In keeping with this, exogenously induced SOCS3 expression blocks LROb signalling in cultured, while LROb signalling is enhanced by SOCS3 knock out. SOCS3 expression has been shown to be increased in obese rodents with Leptin resistance. Leptin itself induces SOCS3 expression and thus modulates (attenuates) its own signalling in obese states, probably explaining the resistance to its actions in the obese. SOCS3 seems to inhibit not only the Leptin>LROb>STAT3 signalling, but also the IRS-2>PI3K signalling which is also a recognised pathway contributing to Leptin-mediated energy balance. (Note that pharmacological inhibition of PI3K blocks Leptin-induced suppression of feeding). Diabetes. 2003 Feb;52(2):227-31 Identification and modification of other regulators of SOCS3 expression (like IL-6, TNF-alpha, fatty acids) could thus serve as a method to overcome Leptin resistance. Further, the importance of SOCS3-mediated inhibition of Leptin's action in the blood-brain-barrier-deficient arcuate nucleus as opposed to elsewhere in the body will also need to be clarified.
The pattern of Leptin administration might be crucial with graded doses of Leptin to compensate for falling Leptin levels in response to weight loss might all be important. Getting past the Leptin resistance by stimulating peptides downstream of Leptin's action (melanocortin agonist , ciliary neurotrophic factor) might be even better options. Using more potent and longer acting Leptin analogs with higher BBB penetrability, or using Leptin sensitizers might be what the future holds. Ultimately, targeting more than one pathway or in effect, polypharmacy, will have to be the way forward in obesity treatment.
Trying to overcome Leptin resistance with higher doses of Leptin seems a straightforward option. But if it is to be successfully accomplished, the factors producing Leptin resistance will have to be better elucidated. To understand the factors contributing to Leptin resistance a brief understanding of the mechanism of Leptin signalling is crucial. Leptin acts through the long form of its receptor LROb. LROb does not have intrinsic enzymatic activity, but it signals through three distinct pathways- J Biol Chem. 2000 May 12;275(19):14563-72 firstly through autophosphorylation of its Tyr985 residue, secondly through autophosphorylation of the Tyr1138 residue, and thirdly through activation of Jak2 (JAK family of tyrosine Kinase). Trends Genet. 1995 Feb;11(2):69-74. Phosphorylation of the Tyr1138 residue of LROb results in recruitment of the latent transcription factor STAT3 to the LROb-Jak2 complex with tyrosine phosphorylation and nuclear translocation of STAT3. STAT3 then activates not only the transcription of POMC, but also that of SOCS3 (Suppressor of Cytokine signalling). The SOCS3 then binds to Tyr985 of LROb producing inhibition of the above mentioned LROb>STAT3 signalling, J Biol Chem. 1999 Oct 15;274(42):30059-65 thus producing inhibition of further Leptin signalling. Mol Endocrinol. 2005 Apr;19(4):925-38. In keeping with this, exogenously induced SOCS3 expression blocks LROb signalling in cultured, while LROb signalling is enhanced by SOCS3 knock out. SOCS3 expression has been shown to be increased in obese rodents with Leptin resistance. Leptin itself induces SOCS3 expression and thus modulates (attenuates) its own signalling in obese states, probably explaining the resistance to its actions in the obese. SOCS3 seems to inhibit not only the Leptin>LROb>STAT3 signalling, but also the IRS-2>PI3K signalling which is also a recognised pathway contributing to Leptin-mediated energy balance. (Note that pharmacological inhibition of PI3K blocks Leptin-induced suppression of feeding). Diabetes. 2003 Feb;52(2):227-31 Identification and modification of other regulators of SOCS3 expression (like IL-6, TNF-alpha, fatty acids) could thus serve as a method to overcome Leptin resistance. Further, the importance of SOCS3-mediated inhibition of Leptin's action in the blood-brain-barrier-deficient arcuate nucleus as opposed to elsewhere in the body will also need to be clarified.
The pattern of Leptin administration might be crucial with graded doses of Leptin to compensate for falling Leptin levels in response to weight loss might all be important. Getting past the Leptin resistance by stimulating peptides downstream of Leptin's action (melanocortin agonist , ciliary neurotrophic factor) might be even better options. Using more potent and longer acting Leptin analogs with higher BBB penetrability, or using Leptin sensitizers might be what the future holds. Ultimately, targeting more than one pathway or in effect, polypharmacy, will have to be the way forward in obesity treatment.