Editors' ChoiceObesity

Giving Leptin a Second Chance

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Science Translational Medicine  22 Jan 2014:
Vol. 6, Issue 220, pp. 220ec14
DOI: 10.1126/scitranslmed.3008433

Touted as the “magic bullet” that would cure obesity, leptin has been the focus of much scientific investigation since its discovery nearly 20 years ago. Although leptin therapy results in astonishing weight loss in individuals with congenital leptin-deficiency, unfortunately it does not have the same effect in individuals with non–leptin-deficient obesity, perhaps because of leptin resistance. Thus, researchers have been attempting to overcome leptin resistance by concomitantly administering other therapeutic agents. To date, attenuation of leptin resistance has been investigated with several pharmacologic agents, but only in the setting of a low-fat diet, which is often difficult to maintain in our obesogenic environment. Therefore, Clemmensen et al. investigated whether administration of a peptide agonist for glucagon-like peptide 1 (GLP-1)/glucagon receptors restores leptin responsiveness in the setting of a high-fat diet.

While on a high-fat diet (HFD), mice with diet-induced obesity (DIO) were given a PEGylated GLP-1/glucagon co-agonist to produce a 15% reduction in body weight. After this initial phase, the DIO mice were randomized to additionally receive PEG-leptin or continue PEG-GLP-1/glucagon alone. The group that received leptin with the GLP-1/glucagon co-agonist lost 18% more weight and demonstrated improved lipid and glucose metabolism as compared with the GLP-1/glucagon monotherapy group. Furthermore, when PEG-GLP-1/glucagon was discontinued and PEG-leptin continued alone, cholesterol, insulin, and liver triglyceride levels all increased in the DIO mice, suggesting that leptin monotherapy failed to maintain the beneficial effects observed with GLP-1/glucagon co-agonism. The authors conclude that GLP-1/glucagon co-agonism restores leptin responsiveness in DIO mice on a HFD.

Thus, even though leptin pharmacotherapy alone has not proven to be an effective treatment for obesity, perhaps combining leptin with other pharmacologic agents may improve its efficacy for weight loss. Certainly, studies in humans will need to be conducted to assess the efficacy and safety of such polypharmacotherapy. In the meantime, perhaps co-agonism with other medications will give leptin a second chance in the fight against obesity.

C. Clemmensen et al., GLP-1/glucagon co-agonism restores leptin responsiveness in obese mice chronically maintained on an obesogenic diet. Diabetes published online 30 December 2013 (10.2337/db13-1609). [Full Text]

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