Obesity Breakthrough: Losing Weight Without Eating Less

Scientists have unraveled how a group of astrocytes, unique brain cells located in the hypothalamus, induces obesity in mice. Furthermore, their research pinpointed a medication that blocked this mechanism, resulting in weight reduction without affecting appetite or food consumption.

The hypothalamus, a vital region in the brain responsible for regulating food intake and energy expenditure, harbors the majority of neurons involved in controlling feeding and body weight.

Gamma-aminobutyric acid (GABA), the predominant neurotransmitter in the hypothalamus, acts on GABA A receptors. As an inhibitory neurotransmitter, GABA plays a crucial role in maintaining the body’s energy balance by determining hunger and satiety signals. When you reach a state of fullness, GABA inhibits the hunger signal, preventing overeating.

Unraveling the Brain’s ‘Hunger Center’ and Its Role in Fat Metabolism

The lateral hypothalamus (LH), also referred to as the lateral hypothalamic area (LHA), is recognized as the brain’s ‘hunger center.’ One of its primary roles is to stimulate feeding behavior; when activated, it induces the sensation of hunger. Although it’s known that LH neurons are connected to fat tissue and are involved in fat metabolism, their precise mechanism in regulating fat metabolism has remained unclear. New research led by the Institute for Basic Science in South Korea has investigated cells in the lateral hypothalamus of mice, with a specific focus on the role played by a particular type of cell called astrocytes in the regulation of fat metabolism.

Within the hypothalamus, there exists a cluster of neurons that specifically expresses the alpha-5 subunit of the GABA A receptor, known as GABRA5. Furthermore, the study revealed that in diet-induced obese mice, there was a notable decrease in the pacemaker firing activity of the GABRA5 neurons. Pacemaker neurons exert influence over neuronal networks by generating intrinsic rhythmic bursts of activity.

A Key to Controlling Weight Through Brown Fat Metabolism

Inhibiting GABRA5 using chemogenetics in mice resulted in reduced thermogenesis in brown adipose tissue (BAT), commonly known as brown fat, leading to fat accumulation and weight gain. Reactivating the hypothalamic GABRA5 neurons, on the other hand, caused weight loss, indicating that these neurons serve as a weight regulation switch.

Upon closer examination, researchers found that reactive astrocytes in the LH were responsible for controlling GABRA5 neuron activity. Unlike typical astrocytes that carry out metabolic and neuroprotective functions in the central nervous system, reactive astrocytes, triggered by pathological conditions, reduce these supportive roles.

In obese mice, these reactive astrocytes exhibited elevated levels of monoamine oxidase-B (MAO-B), an enzyme involved in GABA synthesis by astrocytes. Overexpression of MAO-B inhibited the surrounding GABRA5 neurons. However, when researchers suppressed the MAO-B gene in reactive astrocytes, it reduced GABA secretion, reversing the inhibition. This, in turn, increased thermogenesis in the obese mice’s fat tissues, resulting in weight loss even when they consumed a high-calorie diet. These findings suggest that targeting the MAO-B enzyme produced by reactive astrocytes could offer an effective approach to obesity treatment without impacting appetite.

Identifying Reactive Astrocytes as Obesity Culprits

“Previous approaches to address obesity by targeting the hypothalamus primarily focused on neuronal pathways linked to appetite control,” explained Moonsun Sa, the lead author of the study. “To address this limitation, we shifted our attention to non-neuronal astrocytes and pinpointed reactive astrocytes as the underlying cause of obesity.”

Monoamine oxidase-B (MAO-B) is a well-recognized therapeutic target in the treatment of Parkinson’s disease. A newly developed reversible and selective MAO-B inhibitor, KDS2010, has displayed promise as a Parkinson’s disease treatment and is currently undergoing early clinical trials. In the present study, researchers tested the effects of KDS2010 on their obese mouse models and observed that the drug resulted in a “significant reduction” in fat accumulation and weight without affecting food intake.

“In light of the World Health Organization’s designation of obesity as the ’21st century’s emerging infectious disease,’ we see KDS2010 as a potential next-generation obesity treatment that can effectively combat obesity without suppressing appetite,” commented C. Justin Lee, the corresponding author of the study.

This research was published in the journal Nature Metabolism, and the video below, produced by the Institute for Basic Science, showcases the study’s findings.

Read the original article on: New Atlas

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