Are Adipokines a Biological “Bridge” Linking Mood Disorders and Obesity?

Bipolar disorder (BD) and obesity are all-too-frequent travelling companions. Studies in North America show that more than 60% of people with BD are overweight or obese and that obesity rates are approximately 60% greater in people with BD than in those without BD. The relationship between BD and obesity is not solely a North American phenomenon: it has been demonstrated in studies on every continent except Antarctica. Across races and cultures, the BD-obesity link is consistent and undeniable.

To comprehend this, we must first realize that on 21^st-century planet Earth, it is extraordinarily difficult for anyone to maintain a healthy weight. Modern society is filled with highly palatable, calorie-dense foods that are inexpensive, convenient, and advertised incessantly. Many people have jobs spent behind desks and sedentary pastimes (TV, video games, social media, etc). The combination of high caloric intake and low energy expenditure inexorably leads to weight gain. Unfortunately, this lifestyle is aspirational and easily exported to developing nations with growing middle classes. Think of some of the most densely populated countries in the world, such as China, India, and Brazil, where obesity rates are now growing rapidly. Currently, 2.1 billion people worldwide are overweight or obese, and for the first time in human history, morbidity and mortality from obesity are greater than morbidity and mortality from malnourishment.

As people with BD navigate their way through this world, they face even greater challenges to staying healthy. For example, certain types of symptoms (eg, “atypical” depressive symptoms such as increased sleep and appetite) and comorbid conditions (eg, binge eating disorder) that are particularly common in people with BD increase their likelihood of eating in unhealthy ways and gaining weight. Exacerbating the situation, they are prescribed medications that frequently cause increased appetite and slowed metabolism.

However, the underlying biological mechanisms that connect mood episodes, medications, and weight gain in BD are not well understood. We and our colleagues wondered if a class of hormones called “adipokines” might be involved in this relationship. Adipokines, which are so-named because they are produced by adipose (fat) tissue, play important roles in regulating appetite and metabolism. An exciting recent discovery suggests that some adipokines also have mood-altering properties. For example, one of the best-studied adipokines, leptin, has receptors in brain regions that impact mood and reward. Leptin and another adipokine, adiponectin, has been found to have antidepressant effects in animal models of depression. We hypothesized that if adipokines regulate both mood and appetite, then abnormal adipokine blood levels might lead to both mood episodes and weight gain, functioning as a biological “bridge” between mood disorders and obesity.

To test this hypothesis, we measured the blood levels of five adipokines—leptin, adiponectin, resistin, adipsin, and lipocalin-2—in 53 young people recently diagnosed with BD. We found a number of interesting relationships between adipokines and mood episodes, weight gain, and medications. Among the most important were:

1) Lower levels of leptin and adiponectin—the adipokines with antidepressant properties—predicted a greater risk of depressive relapse over 12 months (as might be expected).

2) Higher levels of leptin and adipsin predicted greater 12-month weight gain.

3) Treatment with second-generation antipsychotics, a class of drugs with well-known metabolic side effects, was associated with higher levels of resistin, an adipokine implicated in the etiology of type II diabetes.

This was one of the first studies to investigate the interplay between adipokines, psychiatric health, and physical health in people with BD. The findings suggest that adipokines may represent a novel pathophysiological mechanism linking mood disorders and obesity. Like any novel study, this one raises additional questions. For instance, if adipokine abnormalities are the “bridge” between mood episodes and weight gain, why did lower leptin predict depression and higher leptin predict weight gain? (This might be related to the fact that the appetite-regulating effect of leptin changes based on a person’s weight. Specifically, in normal-weight people, low leptin predicts weight gain, while in overweight/obese people, high leptin predicts weight gain. Its mood-regulating effects may be more consistent, with low leptin increasing the risk of depression regardless of weight.) In any case, this finding suggests that the effects of adipokines on mood and weight are likely to be complex. Further studies are needed to unravel this complexity and to determine whether adipokines have therapeutic potential as possible mood-regulating molecules.

Financial disclosure:Dr Bond is a consultant for and has received grant/research support from Myriad Genetics. Dr Yatham is on speaker/advisory boards for or has received research grants from AstraZeneca, Bristol-Myers Squibb, CIHR, CANMAT, Dainippon Sumitomo, Eli Lilly, GlaxoSmithKline, Janssen, the Michael Smith Foundation for Health Research, Pfizer, Servier, the Stanley Foundation, and Sunovion.