Obesity begins in the brain and we now know that its development – and treatment – is not the same in men and women. This silent pandemic, which is progressing with type 2 diabetes as one of its main complications, already affects more than a thousand people. … millions of people.
As our environment becomes increasingly obesogenic, the brain continues to operate according to old rules that make it difficult to maintain weight loss, even with revolutionary drugs like semaglutide (Ozempic). This change in outlook transforms current treatments and opens the door to new therapies directly targeted on the brain.
Obesity and overweight are often described as excess fat or a metabolic problem, but their deep origin lies in the central nervous system, particularly in the hypothalamus, the region that acts as an “energy thermostat”. For 95% of our evolutionary history, we have lived in scarcity: Walking, hunting and gathering were essential, and the brain developed very effective mechanisms to defend fat mass, because losing it could mean not surviving.
This “ancestral brain” evolves today in an absolutely opposite environment: high-calorie foods available 24 hours a day, a sedentary lifestyle, chronic stress, sleep disorders and ultra-processed foods. The result is a mismatch between our biology and our lifestyle, amplified in people with a genetic predisposition. Added to this is a point that research is beginning to clearly explore: the system that regulates weight does not work in the same way in men and women.
Hypothalamus: where obesity begins
The hypothalamus integrates hormonal (such as leptin or insulin), metabolic and sensory signals to balance energy ingested and expended. When we lose weight, the brain interprets the situation as a threat and activates powerful defense mechanisms: it increases appetite, reduces energy expenditure and reinforces a “metabolic or obesogenic memory” which pushes us to return to the previous weight.
Therefore, even if the dDiet and exercise are essential to health and they should always be the first intervention, because in many people they are not enough to reverse obesity when brain circuits are already impaired. This point does not invalidate the benefit of the lifestyle: it simply recognizes that, in some cases, the brain needs pharmacological support to escape the obesogenic loop.
When the hypothalamus becomes inflamed – due to stress, a high-calorie diet, lack of sleep, hormonal changes or genetic susceptibility – the activity of neurons that regulate hunger and satiety is impaired. Some people manage to spontaneously return to their initial weight after overeating; Others, however, have a less effective “hypothalamic brake” and accumulate weight more easily. The difference is in the brain.
Gender Perspective: Two Brains, Two Answers
Hypothalamic neurons AgRP (which stimulate hunger) and POMC (which promote satiety) precisely regulate eating behavior. But the hypothalamus is not only a set of neurons: it also includes microglia, the immune cells of the brain, whose role has proven to be decisive. In our group, we have described three phases of microglial activation in the early stages of overnutrition:
Early, rapid and reversible activation.
A sustained inflammatory phase, which alters the satiety circuits.
A final phase of deregulation, in which the mechanisms that should limit weight gain fail.
These phases do not behave the same way in men and women. In rodent models, females show a more stable and protective neuroimmune response, which could explain why they develop obesity later. This pattern is reminiscent of what we observe in premenopausal women. Before menopause, women are at lower risk of metabolic and cardiovascular diseases than men, thanks to the protective effect of estrogen. But protection decreases during perimenopause and menopause, a period that is still very little studied and critical for cardiometabolic risk.
Furthermore, in animal models and cell cultures, we detected very early alterations – in microglia, in lipid signals such as endocannabinoids and in neuronal insulin sensitivity – even before visible changes appeared in peripheral tissues. This suggests that the initial trigger for obesity is cerebral. Integrating this gender perspective is essential to move towards more precise and effective treatments.
New therapies against obesity: incretins and nanomedicine directed to the brain
The treatment of obesity has changed dramatically since 2021 with GLP-1 receptor agonists. Semaglutide and other incretin family drugs, originally developed for type 2 diabetes, have demonstrated a remarkable ability to reduce weight through both peripheral and central actions. However, they have known limitations: gastrointestinal effects, loss of lean mass, weight regain after stopping them or even variable responses depending on the patient’s biological profile.
Recent studies also show gender differences: premenopausal women tend to respond better to these treatments than men.
This poses a challenge: we need therapies that act directly on the brain, with more precision and fewer systemic effects. This is where nanomedicine targeting the brain opens a new horizon. In our group we are developing nanoplatforms (polymeric micelles, protein nanoparticles or intranasal formulations) capable of selectively transporting drugs to the brain. These technologies make it possible to encapsulate molecules which, administered without protection, would be ineffective or toxic, and to direct them towards the cells which control appetite and energy homeostasis.
These approaches could complement or potentiate incretins, reduce side effects, improve compliance, and increase the number of patients who respond. They represent a way of treating obesity from its cerebral origins, with more personalized and lasting interventions.
A new look at an old problem
Obesity is not a lack of willpower, as it is socially stigmatized, nor is it an individual problem. It is a complex disease deeply rooted in a brain adapted to survive in scarcity. Addressing this requires a dual approach: promoting healthy lifestyles and, if necessary, resorting to therapies acting on the brain circuits that regulate weight.
Understanding how the hypothalamus works – and how it fails – will be key to ending the silent pandemic of the 21st century. And it is there, in the brain, that the most promising scientific battle takes place.
Article published in “The Conversation”
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