Role of Leptin in Obesity

January 27, 2011

Louis J. Aronne, MD

In seeking to lose weight, we are often working against our body’s internal logic for survival – a logic that evolved when access to too much food was not the problem.  Fat reserves are a critical energy storage system that enabled our hunter-gatherer forefathers to be without food for significant periods of time.  Hunger serves as a vital motivator to ensure that we actively seek the calories and nutrition we need to survive and reproduce.  

Leptin is a key signaling molecule that controls the relationship between fat reserves, appetite and energy expenditure.  Leptin is released by fat cells as they fill with triglyceride – its circulation in the blood is effectively the fuel gauge that tells the brain how much fat is stored and whether it is enough for the body to perform.  If food intake is high, the balance of available energy increases and fat cells are filled, which in turn increases circulating leptin concentrations and suppresses appetite.

Decreased leptin signaling in the brain leads not just to hunger but also to increased metabolic efficiency.  Thus, as you lose weight, you burn fewer calories based on the same amount of activity.  This, in part, results in the well known phenomenon that after an initial weight loss, maintaining the same rate of loss becomes much more difficult.   

When the role of leptin in energy regulation was first discovered, many thought a pharmacological solution to weight loss was at hand.  All we needed was to administer a drug that acted like leptin to suppress appetite and increase energy expenditure.  However, we soon discovered that, in most cases, obesity is associated with leptin resistance – as leptin levels rise in association with increased fat reserves, fail-safe mechanisms built into the body reduce the effectiveness of leptin signaling.

This concept of leptin resistance is an exciting area of current research, and we are learning that several pathways contribute to leptin resistance.  For example, “fattening foods,” i.e., refined sugar and starch, overload a part of the protein manufacturing machinery (the endoplasmic reticulum) to activate a cellular stress response that inhibits brain leptin signaling.  Too much circulating leptin also saturates the transport mechanisms that allow it to reach the brain and increases the activity of an alternative leptin receptor that inhibits leptin signaling.  In short, through leptin resistance, gaining weight stimulates more weight gain and simply throwing a lot more leptin at the problem does not help.

The search is on for new compounds that will combat leptin resistance and increase the effect of leptin on appetite suppression and energy metabolism.  So-called leptin sensitizers may take many forms. Chemical chaperones that reduce endoplasmic reticulum stress are being examined.   Recent work also suggests that low levels of amylin, a hormone secreted by the pancreas along with insulin, can act synergistically with low levels of leptin to promote weight loss.   And one intriguing study showed that after weight loss, a careful replacement of leptin to pre-weight-loss levels was effective in preventing the fall in metabolic rate that predisposes a person to weight gain. Thus, leptin may indeed become an important part of a pharmacological strategy for weight loss but only once we understand and exploit the body’s biochemical logic in a more sophisticated way.  

Louis J. Aronne, MD is Director, Comprehensive Weight Control Program
at New York Presbyterian Hospital/Weill Cornell Medical Center

For more related articles, click Obesity Perspectives.