Study: gut-brain connections promote fatty food cravings

Background
Obesity is a global health crisis. High BMI increases the risk of stroke, diabetes, and other disorders. Studies link high-sugar and high-fat processed foods to metabolic diseases and comorbidities. Understanding the gut-to-brain route that drives fat consumption could influence therapies to treat obesity and related illnesses. Zuker’s team found that sugar triggers gut-to-brain connections, boosting sweet cravings.

Research
In this study, researchers showed that fat affects fat preference via the gut-brain axis.

Using single-cell data, scientists detected vagal neurons responding to intestinal fat. Next, the scientists monitored vagal neuron activity in response to alternating fat (10 seconds of 10% linoleic acid) and sugar (10 seconds of 500 mM glucose) gut stimulation. Over 1800 vagal sensory neurons from 22 nodoses were analysed.

Researchers used mice to compare gut-to-brain pathways causing fat vs. sugar desire. First, animals were fed artificial sweetener and fat from separate bottles. Next, they examined the fat-sensing circuit’s impact on mouse physiology and behaviour. They produced mice without neural receptors for intestinal fat to prove that neurons mediate gut-to-brain fat reactions.

Data
Mice favoured fat-filled bottles after 48 hours. This behavioural transition showed that, unlike artificial sweeteners, fat continues to excite the brain post-ingestion long after it reaches the gut, driving our desire for it.

Experiments with knock-out mice and molecule-specific inhibitors indicated sequential fat sensing. Fat attaches to gut receptors, which send signals to neurons via the gut-brain axis. Bilaterally activated neurons in the cNST (brain stem) tell the whole brain that fat has been ingested. Fat-activated cNST neurons receive gut-derived signals. Fat infusion activates the cNST in mice.

Bilateral vagotomy eliminated fat-activated neuronal responses in the cNST, establishing the vagus nerve as the fat signal pathway from the gut to the brain. Two groups of vagal neurons operate parallel gut-to-brain communication pathways. 8% of generic neurons responded to fat, sugar, and amino acids, while another 8% responded just to intestinal fat. Two gut-brain pathways for fat sensing were found. Both used GPR40 and GPR120 for fat preference.

Enteroendocrine cells (EECs) in the intestines deliver signals using cholecystokinin (CCK). To confirm this, the researchers used Devazepide, a CCK-A receptor (CCKAR) antagonist. Blocking CCK signalling eliminated all sugar/fat neuron responses, although fat-only responses remained strong.

Conclusions
Interoception, or how the body gets information from interior organs, is not well understood. A gut-to-brain pathway controls fat preference, according to a new study. Fat, like sugar, leverages the gut-brain axis to drive consumption, the authors found.

The study described the innate desire for sweets and fats. The gut-brain axis causes unsatiable hunger for the latter two. Future research should examine how fat-triggered signals travel from the brain stem to the rest of the brain to encourage fat consumption.

 

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