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  • Review Article
  • Published:

Leptin revisited: its mechanism of action and potential for treating diabetes

Nature Reviews Drug Discovery volume 11, pages 692–708 (2012)Cite this article

Subjects

Key Points

  • Leptin is a hormone that is produced by adipose tissue and regulates appetite, body weight, neuroendocrine functions and glycaemia.

  • In this Review, we first discuss data from leptin-based clinical trials. The results from these trials indicate that leptin therapy fails to improve metabolic defects in people who have elevated levels of circulating leptin and hence are leptin-resistant. Conversely, regardless of the disease context, leptin therapy is very effective in improving metabolic imbalances in individuals who have severe hypoleptinaemia.

  • The defects underlying leptin resistance could include impaired transport of leptin across the blood–brain barrier, impaired neuronal leptin signalling in target neurons and altered signalling in downstream targets. Evidence suggests that activation of inflammatory pathways and endoplasmic reticulum stress contribute to the development of leptin resistance.

  • In the presence of insulin, the glucose-lowering effects of leptin are probably mediated by leptin receptor (LEPR)-expressing neurons within the arcuate nucleus of the hypothalamus: specifically, by pro-opiomelanocortin (POMC)-expressing neurons. The neurocircuitry controlled by POMC-expressing neurons could be exploited to lower glycaemia in patients with type 2 diabetes.

  • In the absence of insulin, the glucose-lowering effects of leptin are probably also mediated by LEPR-expressing neurons within the brain, but the biochemical identity of these neurons is still unknown. Once identified, this brain-controlled pathway could be exploited to improve hyperglycaemia in patients with type 1 diabetes.

  • A better understanding of the leptin–CNS (central nervous system)–glycaemia pathway is clearly needed, as this may provide opportunities for the identification of new drug targets and therapeutics that can circumvent the obstacle of leptin resistance and ultimately help to improve the quality and length of life of the millions of people suffering from obesity and/or diabetes.

Abstract

Since the discovery of leptin in 1994, we now have a better understanding of the cellular and molecular mechanisms underlying its biological effects. In addition to its established anti-obesity effects, leptin exerts antidiabetic actions that are independent of its regulation of body weight and food intake. In particular, leptin can correct diabetes in animal models of type 1 and type 2 diabetes. In addition, long-term leptin replacement therapy improves glycaemic control, insulin sensitivity and plasma triglycerides in patients with severe insulin resistance due to lipodystrophy. These results have spurred enthusiasm for the use of leptin therapy to treat diabetes. Here, we review the current understanding of the glucoregulatory functions of leptin, emphasizing its central mechanisms of action and lessons learned from clinical studies, and discuss possible therapeutic applications of leptin in the treatment of type 1 and type 2 diabetes.

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Figure 1: Neuronal leptin receptor activation and inactivation.
Figure 2: Cellular mechanisms that cause leptin resistance in rodents.
Figure 3: Mediators, pathways and mechanisms underlying the antidiabetic actions of leptin.

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Acknowledgements

The authors of this article are supported by grants from the American Heart Association (0930366N to R.C.), the American Diabetes Association (7-09-BS-17 and 7-12-BS-010 to C.B.), the Richard and Susan Smith Family Foundation Pinnacle Program Project (7-05-PPG-02 to C.B.), the Boston Obesity Nutrition Research Center (DK46200 to C.B.) and by grants from the US National Institutes of Health (DK080836 to R.C.; DK60673, DK65743 and DK94040 to C.B.).

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Authors and Affiliations

  1. Department of Internal Medicine, Division of Hypothalamic Research, University of Texas Southwestern Medical Center, Dallas, 75390, Texas, USA

    Roberto Coppari

  2. Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, 1211, Switzerland

    Roberto Coppari

  3. Center for Epigenetics and Metabolism, University of California Irvine, Irvine, 92697, California, USA

    Roberto Coppari

  4. Department of Medicine, Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 02215, Massachusetts, USA

    Christian Bjørbæk

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Glossary

Type 2 diabetes

An illness characterized by insulin resistance, elevated blood levels of glucose, insulin and lipids, and estimated to affect more than 300 million people worldwide.

Type 1 diabetes

An illness characterized by the loss of pancreatic β-cells, lack of insulin, hyperglycaemia, cachexia and ketoacidosis, and estimated to affect millions of people worldwide.

Lipodystrophy

A rare condition that can be inherited or acquired, and is typically characterized by varying adipose tissue loss and distribution.

Hyperleptinaemia

A condition in which leptin levels in the blood are elevated, typically in obesity.

Leptin resistance

A condition in which endogenous and exogenous leptin is less effective at mediating its actions: for example, at reducing food intake or lowering glucose and lipids levels in the blood.

Hypoleptinaemia

A condition in which the level of leptin in the blood is below normal owing to reduced fat mass: for example, in patients with anorexia, lipodystrophy or hypothalamic amenorrhea.

Amylin

A hormone that is co-secreted with insulin from pancreatic β-cells; amylin slows gastric emptying and promotes satiety.

Euglycaemia

Normal levels of glucose in the blood.

Amenorrhea

A condition characterized by the absence of menstrual periods in a woman of reproductive age.

Common obesity

A condition that is characterized by increased body weight due to excess adipose mass, as well as hyperleptinaemia, and is associated with an increased risk of developing type 2 diabetes, cardiovascular disease, cancer and non-alcoholic fatty liver disease.

First-order neurons

In a neurocircuitry aimed at orchestrating responses to changes in a circulating cue, first-order neurons are equipped with the molecular tools to monitor the levels of the circulating cue (for example, they express the cognate receptor for the circulating ligand).

Second-order neurons

In a neurocircuitry aimed at orchestrating responses to changes in a circulating cue, second-order neurons receive direct synaptic inputs from first-order neurons.

Koletsky rats

Rats that are homozygous for a nonsense mutation in the leptin receptor gene, causing lack of leptin receptor function and hence altered metabolic homeostasis.

Hepatic vagotomy

Severing of the hepatic branch of the vagus nerve, resulting in lack of vagal efferent and afferent innervations of the liver.

Insulin-like growth factor binding protein 2

(IGFBP2). A protein that is primarily produced by the liver and that may mediate a proportion of the antidiabetic actions of leptin.

Alloxan

A pyrimidine derivative taken up by cells via facilitated transport through glucose transporter 2; this compound is used in research laboratories to destroy insulin-producing cells in animals.

Polyuria

Abnormally elevated levels of urine production; a condition that can be seen in patients with uncontrolled diabetes.

Hyperketonaemia

A condition characterized by a high level of ketone bodies in the blood; this can be seen after prolonged fasting, the use of a ketogenic diet or due to lack of insulin, typically in individuals with type 1 diabetes.

Pancreatic α-cells

Endocrine cells of the pancreas that secrete the hormone glucagon; the proper functionality of these cells is crucial for preventing a life-threatening reduction in blood glucose levels.

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Coppari, R., Bjørbæk, C. Leptin revisited: its mechanism of action and potential for treating diabetes. Nat Rev Drug Discov 11, 692–708 (2012). https://doi.org/10.1038/nrd3757

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