Article Text

Leptin Deficiency
  1. Susan Blüher, MD*,
  2. Sunali Shah, MD, DSc, FACP, FACE,
  3. Christos S. Mantzoros, MD, DSc, FACP, FACE
  1. From the *Hospital for Children and Adolescents, University of Leipzig, Germany; and †Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
  1. Received May 15, 2009, and in revised form July 20, 2009.
  2. Accepted for publication July 20, 2009.
  3. Reprints: Christos S. Mantzoros, MD, Division of Endocrinology, RN 325, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Ave, Boston, MA 02215. E-mail: cmantzor{at}
  4. The authors did not receive funding for this work from any of the following organizations: National Institutes of Health, Wellcome Trust, Howard Hughes Medical Institute, and others.
  5. This symposium was supported in part by a grant from the National Center for Research Resources (R13 RR023236).

Clinical Implications and Opportunities for Therapeutic Interventions


The discovery of leptin has significantly advanced our understanding of the metabolic importance of adipose tissue and has revealed that both leptin deficiency and leptin excess are associated with severe metabolic, endocrine, and immunological consequences. We and others have shown that a prominent role of leptin in humans is to mediate the neuroendocrine adaptation to energy deprivation. Humans with genetic mutations in the leptin and leptin receptor genes have deregulated food intake and energy expenditure leading to a morbidly obese phenotype and a disrupted regulation in neuroendocrine and immune function and in glucose and fat metabolism. Observational and interventional studies in humans with (complete) congenital leptin deficiency caused by mutations in the leptin gene or with relative leptin deficiency as seen in states of negative energy balance such as lipoatrophy, anorexia nervosa, or exercise-induced hypothalamic and neuroendocrine dysfunction have contributed to the elucidation of the pathophysiological role of leptin in these conditions and of the clinical significance of leptin administration in these subjects. More specifically, interventional studies have demonstrated that several neuroendocrine, metabolic, or immune disturbances in these states could be restored by leptin administration. Leptin replacement therapy is currently available through a compassionate use program for congenital complete leptin deficiency and under an expanded access program to subjects with leptin deficiency associated with congenital or acquired lipoatrophy. In addition, leptin remains a potentially forthcoming treatment for several other states of energy deprivation including anorexia nervosa or milder forms of hypothalamic amenorrhea pending appropriate clinical trials.

Key Words
  • leptin deficiency
  • lipoatrophy
  • neuroendocrine and immune function
  • leptin replacement therapy

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