Mouse Study May Provide Key to Therapies for Leptin Deficiency

A recent mouse study may provide a path to future cell-based therapies for leptin deficiency, according to a report published in Endocrinology.

Researchers led by Charles A. Harris, MD, PhD, of Washington University School of Medicine in St. Louis, point out that metabolic syndrome is a global epidemic, and about 35% of U.S. adults meet the criteria for metabolic syndrome. Obesity in particular is on the rise, resulting from increased food intake coupled with an increasingly sedentary lifestyle, but hormones are implicated as well. “Numerous contributing factors play a role in body composition, yet hormones facilitate many processes regulating energy balance,” the authors write. “A key hormone involved in the regulation of energy balance is leptin.”

Leptin-deficient humans and mice are obese, have diabetes, are infertile, and have hepatic steaosis, according to the authors. There are leptin-replacement therapies, but these are expensive and require daily injections. So the researchers considered another approach: “Because adipocytes are the source of leptin secretion, we investigated whether mouse embryonic fibroblasts (MEFs), capable of forming adipocytes, could be injected into ob/ob mice and prevent the metabolic phenotype seen in these leptin-deficient mice,” they write.

The researchers injected leptin-deficient ob/ob mice once with MEFs and compared them to nontreated ob/ob mice. They found that the treated mice (obRs) had significantly lower body weight than the nontreated mice, due to a decreased in adipose tissue mass. The treated mice has less hepatic steaosis, showed greater glucose tolerance, consumed less food, and had more energy expenditure. “Furthermore, obRs have sustained metabolic protection and restoration of fertility,” the authors write.

The authors write that there are practical implications to this study, namely that the single injection of MEFs could be far preferable for restoring fertility than daily injections of recombinant leptin. “In this report, we demonstrate a simple, effective, and sustainable method of resolving the phenotypic effects of leptin deficiency in the ob/ob mouse model,” the authors write.

The researchers conclude by writing that MEF-derived fat pads are capable of sustaining long-term benefits and may be applied to other types of leptin deficiency, such as lipodystrophy. “Future studies may provide a better understanding of in vivo fat development and aid in the discovery of treatments for metabolic diseases,” the authors write. “Our findings suggest the possibility of future cell-based therapies for patients with leptin deficiency, lipodystrophy, or other mutations in adipose-specific genes.”

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