Faculty & Research

A novel role for the basal forebrain in regulating appetite

Rajalaxmi Natarajan, Ph.D.
Oct 3, 2016

A seminal study published in Nature from the laboratory of Dr. Benjamin Arenkiel, associate professor at Baylor College of Medicine and researcher at the Neurological Research Institute at Texas Children's Hospital, demonstrates that a subset of cholinergic neurons in the basal forebrain act as critical regulators to modulate food intake and control body weight.

Regulating hunger and maintaining proper body weight are crucial for optimal physiological processes that result in a healthy body and mind, as well as prevent diseases like obesity, diabetes, and heart disease. According to National Institute of Diabetes and Digestive and Kidney Diseases, more than two-thirds of adults, and a third of the children in the US are overweight.

Proper diet and exercise are crucial to maintain normal body weight. However, despite that, some people struggle with body weight issues because of genetic susceptibility or hormonal imbalances, which are controlled by specific neural circuits in the brain.

So far, studies on neural control of feeding have focused on the hypothalamus, a major region of the brain crucial for regulating body weight homeostasis. Recently it has been shown that hypothalamic feeding circuits are modulated by the acetylcholine class of neurotransmitters. Interestingly, nicotine, an addictive component of tobacco, and which is a chemical functionally similar to acetylcholine, has long been known to suppress appetite. It is typically observed that smoking cessation is accompanied by weight gain.

While these observations have long hinted at the existence of role of endogenous cholinergic neurons in controlling appetite, it has never been conclusively demonstrated.

Alexander Herman, graduate student in the Arenkiel lab, found that when he abolished the function of a specific group of neurons in the basal forebrain, termed the Diagonal Band of Broca (DBB) to address an unrelated question, the animals began to overeat and gain weight, even though their activity levels remained unchanged, at least until they became too obese to move around.

This surprising observation intrigued the researchers enough to change their line of investigation to dissect the role of these neurons in feeding. In fact, when the researchers exogenously activated DBB neurons in transgenic mice that had been engineered to express a light-gated ion channel protein, they observed a significant decrease in the amount of daily food intake along with a rapid loss of body weight in these mice.

Furthermore, they found that DBB cholinergic neurons form functionally important connections to the hypothalamus, a site of AgRP and POMC neurons, which are well-established key players in regulating hunger and feeding behaviors.

In conclusion, the authors have serendipitously unearthed a novel function for DBB neurons of the basal forebrain in feeding behavior. This study shows that DBB neurons may indeed act as master regulators or orchestrators of the well-studied hypothalamic-cholinergic circuit. Moreover, acetylcholine is a known powerful modulator of neural pathways that regulate reward, aversion and addiction, and the authors hypothesize that they may have uncovered the endogenous cholinergic signaling that controls food addiction (e.g., obesity) or food aversion (e.g., anorexia, bulimia, binge eating etc.).

The most exciting aspect of this study is the potential for translating it to clinical therapy for obesity and food-related addictive or aversive behaviors. Although rigorous studies are needed to validate the observations in humans, it is conceivable that this study could be used as a foundational basis in the future for targeting DBB neurons to combat obesity and other eating disorders.

This study has opened a fascinating possibility that inhibiting or activating DBB neurons using pharmacological agents or other methods such as deep brain stimulation, a nonsurgical treatment currently used to treat Parkinson's, could ameliorate addictive or aversive eating habits.

These findings were discussed in an article published recently in the Wall Street Journal - read it here

See Baylor College of Medicine and Texas Children's Hospital's joint news release