Sunday, March 25, 2012

Leptin and the Body Fat Setpoint

About Leptin

The 'body fat setpoint' is a theory based on observations that: (1) people and other animals maintain a fairly constant weight despite not counting calories and day-to-day variations in calorie intake and expenditure; and (2) after periods of overfeeding or underfeeding people will return to roughly their previous weight (see next section).

Leptin is a homeostatic controller of stored body fat and the main driver behind the body fat setpoint.  Leptin is released by our fat cells (adipocytes) roughly in proportion to stored body fat levels.  Leptin can enter the brain, specifically the arcuate nucleus of the hypothalamus*, where it activates POMC neurons and inhibits AgRP/NPY neurons, both of these actions promote a decrease in appetite (food intake) and an increase in energy expenditure (see below)

* A part of the brain that is responsible for homeostasis of other things such as steroid hormones, body temperature and the circadian rhythm)

How Leptin Regulates Body Fat

Following overfeeding there is an increase body fat, which leads to an increase in leptin.  The higher leptin levels result in a decrease to appetite and an increase to energy expenditure, so that when the overfeeding period ends people eat less and burn more calories, which creates necessary calorie deficit for weight loss.  This weight loss continues until the body fat setpoint is reached, which is when leptin returns to baseline levels


Ad Libitum means ‘at one’s pleasure’, or how much one chooses to eat when food is freely available

Following underfeeding (calorie restriction) there is an decrease body fat, which leads to an decrease in leptin.  The lower leptin levels result in an increase to appetite and a decrease to energy expenditure, so that when the underfeeding period ends people eat more and burn fewer calories, which creates necessary calorie surplus for weight gain.  This weight gain continues until the body fat setpoint is reached, which is when leptin returns to baseline levels


This explains why it’s so difficult to maintain weight loss caused by deliberate calorie restriction

“With such a powerful system in place to keep body fat mass in a narrow range, a major departure from that range implies that the system isn't functioning correctly. In other words, obesity has to result from a defect in the system that regulates body fat, because a properly functioning system would not have allowed that degree of fat gain in the first place.” – Stephen Guyenet 

This is also why wild animals and hunter-gatherers pretty much remain lean all year round and is another refutation of the thrifty gene hypothesis.  It’s normal for this system to work. 

Defects in Leptin Signalling >> Obesity

Examples of this system not working are mice with a genetic mutation where they can’t produce leptin (ob/ob) and mice with nother genetic mutation where they don’t have leptin receptors (db/db).  Both of these mice are very obese.

ob/ob left, wild type right

But these mutations are extremely rare.  Most human obesity isn't caused by these mutations and is characterised by very high leptin levels (due to having lots of body fat) and a lack of significant weight loss in response to leptin administration.  This suggests that the defect in most human obesity in leptin resistance (LR) (analagous to insulin resistance) [3].  When mice are fattened through diet induced obesity (DIO)* mechanisms of leptin resistance, such as various signals that inhibit the signal transduction of leptin [3], inflammation [4] and apoptosis [5] of hypothalamic neurons, occurs before obesity, suggesting leptin resistance causes obesity, but also maintains obesity.

So then, what causes leptin resistance?

* Obesity researchers need a way of inducing obesity in animals quickly and reliably.  Many studies use a special diet called ‘high fat diet’ or ‘HFD’, which is high in fat but made from refined ingredients.  They use it because mice/rats consistently eat many more calories on this diet [6].  Note the difference between ‘high fat diet’ (a name) and ‘a high fat diet’ (a description of a diet that can be generalised).  There’s enough evidence to suggest humans can lose weight on high fat diets and another way of explaining HFD is ‘diet induced obesity’ (DIO), so I’ll use DIO instead of HFD. 

Further Reading:
(1) Why Do We Eat? A Neurobiological Perspective. Part III
(2) The Body Fat Setpoint

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