What is the Best Way to Reduce Body Fat? Leptin and The Hypothalamus

Recently, Robb Wolf – author of the New York Times Best Seller, The Paleo Solution – sat down for a conversation with Stephan Guyenet and myself – co-creators of the Ideal Weight Program – to talk about weight loss, and why it’s so hard to maintain results. A big focus of the conversation, and the program, centers on an area of the brain called the hypothalamus. Here, I write a bit more about this brain area, and describe why it’s so important for any and all serious discussion on the subject of weight regulation. You can listen to our podcast at the bottom of the article.

The hypothalamus contains different cell groups, each of which perform special tasks. As signals make their way to it, the hypothalamus compares that information to pre-programed ideal values. These ideals are most commonly referred to as ‘setpoints.’ When a signal of one of the monitored systems deviates from its setpoint, the hypothalamus initiates a program to right the ship. This process is called homeostasis– the aim to maintain internal balance in the face of challenges. Listen to the interview posted below to hear Stephan discuss a home thermostat as analogous to what happens here.

Because it is highly sensitive to signals informing it of both the external environment and internal state, when the body is placed in an environment with which it is unfamiliar, ‘normal’ signaling of the hypothalamus can become problematic. For example, the hypothalamus evolved to produce the hormone melatonin when the sun goes down and darkness falls. Artificial light (such as an e-reader screen) tells it that it is still daytime, preventing melatonin secretion. The hypothalamus is doing what it’s supposed to do– suppress melatonin secretion in the presence of light– but the unnatural light stimulus makes its response inappropriate. And this sort of ‘proper functioning but abnormal environment’ can be highly problematic to our health.

At the Ancestral Health Symposium of 2014, Josh Turket, MD gave a very interesting talk entitled Migraine as the Hypothalamic Distress Signal. In his talk, he discusses how migraine attacks are triggered within the hypothalamus when the signals it receives are outside the bounds of what human’s experienced during the course of our evolution. This creates a state where the body is no longer able to generate homeostasis, and in this case, migraine-prone people get a migraine. Interestingly, he also notes that people who are obese are nearly twice more likely to experience migraine!

At its disposal, it has three main mechanisms by which it can change your physiology. First, it controls the autonomic nervous system. Second, it can control hormones. Lastly, it can alter the likelihood that you will engage in certain behaviors. If you’re cold, the hypothalamus can increase your motivation to put on a sweater.

While the different cell groups of the hypothalamus perform specific tasks, they also gossip with one another. For example, when the cell groups responsible for feeding and energy balance detect a reduction in stores of body energy (fat), and lack of energy in the digestive tract (from food), these energy-sensitive neurons modify the activity of a variety of other cell types in the hypothalamus. This is why you can observe a drop in core body temperature after weight loss, and see increased wakefulness in a reduced-calorie state.

Some of the earlier work showing its role in feeding and metabolism was performed by John Brobeck and others in the 1930s and 1940s. In their research, lesions of the ventral medial hypothalamus (VMH) caused their rodents to become obese. Why did they gain fat? Well, while the animals were less physically active, the majority of the effect was explained by the fact that these animals overate. Why did these animals overeat when this part of the brain was destroyed?

This observation led the what became the lipostasis theory, which stated that the level of fat maintained on the body is controlled by a feedback loop. In this theory, the amount of stored fat is sensed by the hypothalamus, which adjusts food intake and energy expenditure to maintain a constant body weight. If you destroy the receiver of the signal (lesioning the VHM), the system doesn’t work. That’s exactly what happened when these researchers removed this key center of the hypothalamus: animals didn’t detect the stores of energy present on the body, and this, in turn, caused them to overeat. Another way to say this is that the body has a way to detect the amount of stored fat and alter its physiology to compensate for changes. While it seemed clear that a feedback loop was operating to control the body fat level, the signal itself wasn’t identified until years later when researcher Jeffrey Friedman of Rockefeller University identified the hormone leptin.

Leptin is the primary signal that tells the brain how much fat is stored on the body. It is a hormone that is (primarily) produced by fat tissue, and the amount that is produced depends on how much fat you carry. As you gain fat, the amount of leptin you produce increases. As you lose fat, the amount decreases. Once it’s produced, leptin enters into the circulation where a transport protein carries it from the bloodstream into the brain. A primary site of its action is the arcuate nucleus of the hypothalamus. I won’t go into detail as to all the physiological players (sites, signals, interactions) involved in the process, but rather, I will described the general way in which the brain detects the amount of energy in the body, and reacts to it.

Imagine that the arcuate nucleus contains a seesaw (Figure 1). On one side of the seesaw is a program to increase fat storage. On the other side is a program to decrease it. Leptin affects the neurons on both sides of the seesaw. It suppresses the program designed to increase fat stores, and activates the program to decrease it. So what do you think happens when you lose fat, and therefore produce less leptin? The absence of leptin, and its dual effects, shifts the balance to increase fat storage. This is one of the primary reasons why people regain fat after losing it. But, if this mechanism was working correctly, wouldn’t it be hard to gain weight in the first place? If you did, wouldn’t a properly working seesaw push the weight back down towards your setpoint? To explore why we gain weight and have a hard time losing it, we need to discuss leptin resistance.

With leptin resistance, the body becomes oblivious to the leptin signal that is present. Either leptin doesn’t get across the blood brain barrier (which is necessary in order for the brain to respond to it), or the brain itself becomes insensitive to it. This may create a situation not too different from what was seen with Brobeck’s rats – there is a communication problem between the available signal (leptin) and the receiver (the sensitivity of the hypothalamus to leptin).

A variety of lifestyle factors may affect leptin resistance, including sleep fragmentation, inactivity, calorie surplus, and certain levels of dietary fat (but not other levels). Researchers believe that resistance to leptin is caused by an increase in inflammation and stress in the brain. This process is thought to contribute to an elevated body fat setpoint. In other words, the common phenomenon of a person gaining weight, and having a hard timing losing it or keeping weight loss results, might in part be explained by an energy balance system that has become insensitive to the leptin signal.

Interestingly, in adults, the energy balance circuit is remodeled by ongoing generation of new neurons. New neurons replace old ones. In animal models of diet induced obesity, the replacement of old neurons by new ones is suppressed, and this may contribute to an elevated weight setpoint. The good news is that weight loss itself can promote more active remodeling. Interestingly, despite the degree of lost weight, the diet used during the weight loss period affects the amount of neuron remodeling that takes place, which affects what happens after the weight is lost. And this is just one of the reasons why not every weight loss program is alike, so choose your weight loss program carefully.

For the field, an important goal is to find solutions to reduce inflammation and stress within the hypothalamus, and therefore promote leptin sensitivity. Additionally, promoting neuron remodeling may help lower the weight setpoint, making it easier to achieve and sustain meaningful weight loss. More research is needed on this topic but there are signs that this might be achievable, at least partially, by conforming to certain diet and lifestyle habits (McNay et al., 2012, Ropelle et al., 2010); habits which we try to leverage in the Ideal Weight Program. My suspicion is that this does happen when a person loses weight, sticks with the right diet and lifestyle, and is able to maintain the new weight comfortably. Conversely, this probably doesn’t happen when a person loses weight, and feels miserable until their weight is back where they started in the first place. In my current view, all weight loss strategies should keep these ideas in mind.

In the interview below, Robb, Stephan and I discuss some of these points in more detail, the Ideal Weight Program that Stephan and I developed, and announce that we’re taking questions about weight loss and the weight loss program here. Anyone can submit a question and we will create a second audio interview where we respond to the questions for members of the program. The second audio interview will be posted for members before the end of February, 2015. In the meantime, please enjoy the first interview here: