On Leptin Resistance and Obesity

Named after leptos, the Greek term for “thin,” leptin is a hormone released by your fat cells.

Although it has a number of functions, one of leptin’s main roles is to let your brain know how fat you are. When you lose fat, leptin levels drop. When you gain fat, leptin levels go up.

The amount of leptin in your blood is strongly linked to fat mass. The fatter you are, the higher your leptin levels. The link is even stronger to subcutaneous fat (the name given to fat stored under your skin) which has been shown to secrete more leptin than other sources of fat, such as visceral fat [10].

Leptin levels are 3-4-fold higher in women than in men with a comparable body mass index [4]. This appears to be due to the influence of hormones as well as differences in body fat distribution between men and women.

Before the discovery of leptin, body fat was seen as a lifeless source of energy.

However, work by researchers at the Rockefeller University in the 1990’s led to a radical change in perspective.

Both of the mice in the picture below have a genetic defect that predisposes them to gain weight. When they were injected with leptin — the hormone this “broken” gene normally produces — the mice lost weight.

leptin resistance and obesity

After four and a half weeks of daily injections, the mouse on the left, which did not receive leptin, weighed approximately 67 grams. The mouse on the right, who received daily injections of leptin, weighed 35 grams.

As well as being affected by total body fat levels, leptin is also under the influence of your diet.

Levels will rise and fall quite rapidly in response to both overfeeding and underfeeding [17, 18]. After the initial drop in response to underfeeding, leptin declines at a rate that’s linked more closely to the loss of fat.

In one trial, 12 overweight but otherwise healthy women followed a low-calorie diet for three months [6]. After just seven days, leptin levels dropped by around 50%. That’s despite the fact that body fat dropped by only 0.5%.

In other words, leptin concentrations don’t always decrease at the same rate as body fat.

The researchers also found that the desire to eat doubled in response to the diet. And the volunteers reporting the greatest increase in hunger were those with the largest drop in leptin.

Leptin is just one of the hormones responsible for this increase in hunger. It also interacts with other hormones, such as ghrelin and CCK, which have an effect on your appetite [16].

Leptin appears to respond to any form of calorie deficit.

It doesn’t seem to matter too much whether that deficit is created by diet or exercise [3, 20]. The bigger the deficit, the bigger the size of the drop in leptin.

Comparing the effects of two different exercise sessions, researchers from Wake Forest University found that a bout of exercise burning approximately 900 calories led to a greater drop in leptin than a workout that burned only 200 calories [19].

When you overfeed for a few days, leptin levels will rise a lot more quickly than any lost fat is regained [7]. And the type of food you overfeed with also has a big impact on leptin production.

Leptin levels appear to correlate closely to blood sugar (glucose) levels. In other words, when blood sugar levels rise, so does leptin [21, 22, 23]. Three days of overfeeding with carbohydrate raises leptin levels, whereas overfeeding with fat has no significant effect [26].

A daily diet containing high-fat, low-carbohydrate meals (60% fat, 20% carbohydrate) appears to reduce leptin levels compared to an isocaloric diet containing low-fat, high-carbohydrate meals (20% fat, 60% carbohydrate [27].

Researchers have also found that a diet rich in carbohydrates with a high glycemic index raises leptin to a greater extent than a diet containing low glycemic index carbohydrates [24].

More interesting still, drinks sweetened with high fructose corn syrup (a blend of fructose and glucose) don’t elevate 24-hour leptin concentrations to the same degree as drinks sweetened with glucose [25].

Alcohol has also been shown to inhibit the secretion of leptin [28], which might explain why alcohol increases your appetite and subsequent calorie intake over 24 hours when consumed as an apéritif [29].

Unfortunately, you can’t just take a leptin pill and hope that your weight problems will be solved forever.

For one thing, leptin can’t be taken orally because your stomach will break it down. For leptin to be effective, you need to inject it. Every day. For life. This is not only very inconvenient but also very expensive.

And, despite the fact that Amgen Pharmaceuticals plunked down $25 million for the rights to leptin, the hormone has turned out to be anything but obesity’s “magic bullet.”

While some studies show that using injections to raise leptin helps with appetite control and weight loss [11, 12], other trials show they have little or no effect [13, 14, 15].

Although it might seem counterintuitive, many obese individuals actually have high levels of leptin. On the face of it, this appears to blow all of the theories regarding leptin and weight loss out of the water.

After all, if obese people have high levels of leptin, why are they obese in the first place?

Part of the problem is caused by a phenomenon called leptin resistance.

This appears to be due to decreased leptin transport into the brain or some kind of defect in the way leptin receptors respond to the hormone [2]. In other words, some people don’t respond to leptin in the way they should.

It appears that leptin isn’t active in the part of the brain that controls eating behavior. When leptin is constantly elevated, which it will be in most overweight or obese people, the transporters that help leptin to cross from the blood into the brain become saturated. There may also be genetic causes that contribute to leptin resistance.

In either case, raising leptin levels above the normal physiological range isn’t going to help much.

Leptin injections may, however, have a role to play in preventing leptin from falling during a period of weight loss. In one study a low-dose course of “replacement” leptin reversed some of the metabolic changes that occur during weight loss [9]

In the study, four subjects (2 men and 2 women) were fed 800 calories per day until they’d lost 10% of their initial weight. This led to a drop in both leptin and thyroid hormone concentrations, along with a reduction in the metabolic rate.

For the next five weeks, subjects received low-dose leptin injections twice a day to bring leptin back to pre-diet levels. These “replacement doses” of leptin reversed the drop in energy expenditure and thyroid hormone levels. The participants also continued to lose fat while preserving muscle tissue.

To summarize and review, leptin signals the brain about how much fat is stored in your body (more fat means higher leptin levels) and how much you’re eating (if you burn more calories than you consume, leptin levels will drop).

It looks like a drop in leptin production acts as a signal of negative energy balance (you’re burning more calories than you’re taking in) and low energy reserves, rather than indicating a positive energy balance and increased energy reserves.

And a drop in leptin concentrations seems to have a bigger impact on your body than increasing leptin levels above the normal physiological range [5].

“The primary functional role of leptin is apparently to defend — not reduce — body fat by increasing food seeking and decreasing energy expenditure when fat stores are insufficient,” writes Dr. Michael Rosenbaum in the Journal of Clinical Investigation [30].

“Physiological responses to concentrations of leptin below and above this threshold are very asymmetrical: decreased concentrations of leptin trigger full-strength counterregulation to what is ‘perceived’ as a threat to survival; concentrations of leptin above the threshold — signaling ‘sufficient’ or excess fat stores — are not responded to vigorously, or at all.”

In other words, your body will fight harder against losing fat than it will against gaining fat. That’s why most people find it a whole lot easier to get fat than they do to get lean.

Although some have referred to leptin as an “anti-obesity” hormone, it’s probably more accurate to label it as an “anti-starvation” hormone that tells your brain what to do when energy is in short supply.


If you want less flab and more muscle when you look down at your abs (or where they should be), check out The Flat Belly Cheat Sheet.

It's a straight-to-the-point PDF, written in plain English, that tells you exactly how to get rid of belly fat. To download a free copy, please click or tap here.

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Christian FinnChristian Finn holds a master's degree with distinction in exercise science, is a former personal trainer and has been featured on BBC TV and radio, as well as in Men's Health, Men's Fitness, Fit Pro, Zest, and Perfect Body magazine.

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