Collage of three adult women and a girl with GL and PL showing varying appearances of the disease with complete or partial lack of subcutaneous fat

Generalised or partial
lipodystrophy (GL or PL)

The pathophysiology

Physiological fat storage

Normally, excess energy and fat is stored in adipose tissue. When the storage capacity is exceeded, the excess energy is stored as ectopic fat.1,2

Hormone secretion

Fat cells are endocrinally active and secrete hormones (adipokines), including leptin. Leptin is an important regulator of energy homeostasis, lipid and glucose metabolism, fertility and many other bodily functions.3,4

GL or PL are always connected to a lack of subcutaneous adipose tissue to store energy. But the degree can vary according to the type of lipodystrophy.3

Absence of subcutaneous body fat

If there is little or no adipose tissue as in lipodystrophy, excess energy is stored ectopically e.g. in the liver and heart, kidneys, pancreas and muscles. The direct lipotoxicity connected to this leads to serious comorbidities.1,3


Leptin deficiency

A leptin deficiency caused by the loss of fatty tissue makes a significant contribution to the metabolic disorders in GL and PL and also leads in particular to insatiable hunger and excess food intake, which exacerbates the metabolic comorbidities further. Expressions of leptin deficiency are insulin resistance with diabetes mellitus (possibly with acanthosis nigricans, PCOS), hypertriglyceridaemia and hyperphagia.1,5,6

Diabetes mellitus?




reduced subcutaneous
fat or unusual
fat distribution?





1 Nolis T. Exploring the pathophysiology behind the more common genetic and acquired lipodystrophies. J Hum Genet 2014;5:16-23.

2 Oral EA, Chan JL. Rationale for leptin-replacement therapy for severe lipodystrophy. Endoc Pract 2010;16:324-333.

3 Brown et al., The Diagnosis and Management of Lipodystrophy Syndromes: A Multi-Society Practice Guideline. J Clin Endocrinol Metab. 2016; 101: 4500 – 4511.

4 Mantzoros CS, Magkos F, Brinkoetter M, et al. Leptin in human physiology and pathophysiology. Am J Physiol Endocrinol Metab 2011;301:E567–84.

5 Rodriguez AJ, Mastronardi CA, Paz-Filho GJ. New advances in the treatment of generalized lipodystrophy: role of metreleptin. Ther Clin Risk Manag 2015;11:1391-400.

6 Paz-Filho G, Mastronardi CA, Licinio J. Leptin treatment: facts and expectations. Metabolism 2015;64:146-56.