A recent study published in Nature Metabolism has uncovered distinct neuronal populations in the hippocampus (HPC) that respond specifically to sugar and fat intake. This discovery could pave the way for new strategies in controlling obesity by targeting the brain’s response to these nutrients.
Survival depends on the ability to acquire sufficient food to meet metabolic needs. Cognitive mapping—the ability to navigate to food sources—provides a survival advantage. Associating specific cues with food consumption leads to heightened motivation to eat, a process that has been adapted for survival. However, in today’s food environment, where high-fat and high-sugar foods are readily available, this adaptive behavior can contribute to overeating and obesity. Understanding how the brain forms memories of food-related cues may help address these issues.
The hippocampus, a brain region essential for forming memories and cognitive mapping, has been implicated in food intake regulation. Research has shown that disrupting the HPC in rats can lead to increased food consumption and body weight. Additionally, diets rich in fats and sugars have been shown to impair memory and spatial learning tasks dependent on HPC function.
The researchers sought to determine whether the HPC neurons responsive to sugar and fat have orexigenic (hunger-stimulating) functions. The team studied Fos expression—an indicator of neuronal activity—following intragastric (IG) infusions of sugar, fat, or saline in mice. Fos levels increased in distinct populations of neurons in the dorsal hippocampus (dHPC) in response to both sugar and fat, suggesting that these neurons are activated by specific nutrients.
Further experiments revealed that nutrient-induced Fos expression was significantly lower in mice that had undergone vagotomy (surgical disruption of the vagus nerve), indicating the importance of the vagus nerve in relaying nutrient signals to the HPC.
By using a FosTRAP mouse model, the researchers identified two separate neuronal populations in the dHPC that were responsive to either sugar or fat. These neurons were predominantly labeled with the vesicular glutamate transporter 1 (vGLUT1), a marker for excitatory neurons, while less than 5% of the nutrient-responsive neurons showed expression of gamma-aminobutyric acid (GABA), a neurotransmitter associated with inhibitory neurons.
To explore the role of these neurons in regulating food intake, the researchers selectively ablated the sugar- or fat-responsive neurons in the FosTRAP mice using a Cre-dependent virus. The results showed that mice with ablated sugar-responsive neurons reduced their sugar intake by 50% without affecting fat consumption. In contrast, mice with ablated fat-responsive neurons reduced their fat intake by 40%, with no effect on sugar consumption.
The team also tested whether these neurons play a role in food location memory by adapting a food-cup location memory task. Mice were trained to associate a location with either sugar or fat droplets. While control mice were able to recall the location of the nutrient-paired dish, mice with ablated sugar-responsive neurons failed to do so. Interestingly, these ablations did not affect memory related to non-food objects, highlighting that these neurons are specific to food-related memory.
Further experiments confirmed that both sugar- and fat-responsive neurons are orexigenic, promoting the consumption of high-fat, high-sugar (HFHS) diets. Mice with ablated sugar-responsive neurons consumed less HFHS, showing reduced meal frequency, while fat-responsive neuron ablation resulted in smaller meal portions.
This study highlights the critical role of the dorsal hippocampus (dHPC) in regulating food intake, revealing distinct neuronal populations that respond to sugar and fat. While both types of neurons promote food consumption, their effects on macronutrient choice and motivation differ. Fat-responsive neurons primarily influence motivation, while sugar-responsive neurons are more involved in spatial memory.
By identifying these nutrient-responsive populations, the study offers potential therapeutic targets for combating obesity. The research emphasizes the need for further exploration into how the brain’s regulation of food intake can be modulated to prevent overeating and the associated health risks.
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