Is the adage “calories in, calories out” true? The short answer is yes, but the full story is more nuanced.

From the moment food touches your tongue to the time it leaves your body, your digestive system and gut microbiome work to extract its nutrients. Enzymes in your mouth, stomach and small intestine break down food for absorption, while microbes in your large intestine digest the leftovers.

“Calories in, calories out” refers to the concept that weight change is determined by the balance between the calories you consume and calories you expend. This includes not only the number of calories you eat due to appetite and absorb via digestion, but also how well those absorbed calories are burned through metabolism.

Recent research indicates that a significant factor influencing people’s variable appetites, digestion and metabolism are biologically active leftover components of food, known as bioactives. These bioactives play a key role in regulating the body’s metabolic control centers: your brain’s appetite center, the hypothalamus; your gut’s digestive bioreactor, the microbiome; and your cells’ metabolic powerhouses, the mitochondria.

I’m a gastroenterologist who has spent the past 20 years studying the gut microbiome’s role in metabolic disease. I’ll share how dietary bioactives help to explain why some people can eat more but gain less, and I’ll offer some dietary tools to improve metabolism.

Ruminating on appetite and digestion

Research has shown that consuming whole foods still “packaged” in their original fibers and polyphenols – the cellular wrappers and colorful compounds in plants that confer many of their health benefits – leads to more calories lost through stool, when compared with processed foods that have been “predigested” by factories into simple carbs, refined fats and additives.

This is one way calorie-free factors influence the “calories in, calories out” equation, which can be beneficial in a society where calorie intake often exceeds needs. Eating more whole foods and less processed foods simply lets you eat more because more of those unprocessed calories go out the other end unused.

Fiber and polyphenols also help regulate your appetite and calorie intake through the brain. Your microbiome transforms these leftover bioactives into metabolites – molecular byproducts of digestion – that naturally decrease your appetite. These metabolites regulate the same gut hormones that first inspired the popular weight loss drugs Wegovy, Ozempic and Mounjaro, controlling appetite through your brain’s satiety center, the hypothalamus.

Processed foods lack these bioactives and are further formulated with salt, sugar, fat and additives to be hyperpalatable, causing you to crave them and eat more.

Mitochondrial maestros in the middle

A full accounting of calories also depends on how effectively your body burns them to power your movement, thoughts, immunity and other functions – a process largely orchestrated by your mitochondria.

Healthy people typically have high-capacity mitochondria that easily process calories to fuel cellular functions. People with metabolic diseases have mitochondria that don’t work as well, contributing to bigger appetites, less muscle and increased fat storage.

They also have less of a mitochondria-rich type of fat called brown fat. Rather than storing calories, this fat burns them to produce heat. Less brown fat may help explain why some people with obesity can have lower body temperatures than those who aren’t obese, and why there has been a decline in average body temperature in the U.S. since the industrial revolution.

Healthy mitochondria that burn more calories might also help explain why some people can eat more without gaining weight. But this raises the question: Why do some people have healthier mitochondria than others?

Your mitochondrial health is ultimately influenced by many factors, including those usually associated with overall well-being: regular exercise, adequate sleep, stress management and healthy eating.