First liver-generated hormone to work with brain to control sugar-intake identified.


The recent surge in obesity prevalence has been greatly influenced by food intake and diet composition. Energy from food comes in three macronutrient forms- fat, protein, and carbohydrate.  Over the past 50 years, excessive consumption of carbohydrate in the U.S. has been linked with metabolic disease. However, although there is abundant physiological evidence for independent appetites for fats, carbohydrates, proteins, and micronutrients, the molecular mechanisms that determine appetite for specific nutrients are largely unknown.  Now, a study led by researchers at the University of Iowa shows that a hormone produced by the liver, namely fibroblast growth factor 21 (FGF21), suppresses the consumption of simple sugars. The team state that FGF21 is produced in the liver in response to high carbohydrate levels where it then enters the bloodstream to send a signal to the brain to suppress the preference for sweets.  The opensource study is published in the journal Cell Metabolism.

Previous research show that it was first proposed in the 1960s that the liver functions to regulate food intake and carbohydrate preference. The so-called ‘hepatostatic theory’ postulated that hepatic signals from the liver provide information about carbohydrate reserves.  Since then multiple groups have confirmed and expanded on the role of the liver in carbohydrate preference and food intake. Although carbohydrate is an important fuel source, excessive carbohydrate consumption can lead to hepatic toxicity and numerous other chronic diseases including obesity and diabetes. Therefore, just as there are mechanisms to promote carbohydrate intake, it is hypothesized that mechanisms likely exist to reduce carbohydrate.  Based on this, human genome-wide studies found associations between certain DNA mutations and people’s intake of specific macronutrients; two of these mutations were located near the FGF21 gene.  The current study identifies the role of the FGF21 hormone, an endocrine hormone which regulates energy homeostasis, in regulating macronutrient preference.

The current study used genetically-engineered mouse models and pharmacological approaches to examine the role of FGF21 in regulating sugar cravings. The researchers state that in normal mice, they injected FGF21 and gave the mice a choice between a normal diet and a sugar-enriched diet. Results show that the group of mice didn’t completely stop eating sugar, however, they ate seven times less than normal.

The team also studied genetically-modified mice that either didn’t produce FGF21 at all or produced a lot of FGF21, over 500 times more than normal mice. The lab state that the genetically-modified mice had a choice between the same two diets as the normal mice. Data findings show that the mice that didn’t produce FGF21 at all ate more sugar, whereas the mice that produced a lot of FGF21 ate less sugar.  Results show that FGF21 decreases appetite and intake of sugar, however, FGF21 does not reduce the intake of sucrose, fructose and glucose equally; FGF21 also doesn’t impact the intake of complex carbohydrates.

The team surmise that their findings show that FGF21 sends signals to the brain, with additional work needed to identify the precise neural pathways that regulate FGF21’s ability to manage macronutrient preference.  They go on to add that they are now focused on the hypothalamus, a section of the brain responsible for regulating feeding behavior and energy homeostasis.  For the future, the researchers state that they would also like to see if additional hormones exist to regulate appetite for specific macronutrients like fat and protein and how those signals intertwine to regulate the neural sensing of different macronutrients.

Source: UI Carver College of Medicine

 

The liver is an important integrator of nutrient metabolism, yet no liver-derived factors regulating nutrient preference or carbohydrate appetite have been identified. Here we show that the liver regulates carbohydrate intake through production of the hepatokine fibroblast growth factor 21 (FGF21), which markedly suppresses consumption of simple sugars, but not complex carbohydrates, proteins, or lipids. Genetic loss of FGF21 in mice increases sucrose consumption, whereas acute administration or overexpression of FGF21 suppresses the intake of both sugar and non-caloric sweeteners. FGF21 does not affect chorda tympani nerve responses to sweet tastants, instead reducing sweet-seeking behavior and meal size via neurons in the hypothalamus. This liver-to-brain hormonal axis likely represents a negative feedback loop as hepatic FGF21 production is elevated by sucrose ingestion. We conclude that the liver functions to regulate macronutrient-specific intake by producing an endocrine satiety signal that acts centrally to suppress the intake of “sweets.”  FGF21 Mediates Endocrine Control of Simple Sugar Intake and Sweet Taste Preference by the Liver.  Potthoff et al 2015.

The liver is an important integrator of nutrient metabolism, yet no liver-derived factors regulating nutrient preference or carbohydrate appetite have been identified. Here we show that the liver regulates carbohydrate intake through production of the hepatokine fibroblast growth factor 21 (FGF21), which markedly suppresses consumption of simple sugars, but not complex carbohydrates, proteins, or lipids. Genetic loss of FGF21 in mice increases sucrose consumption, whereas acute administration or overexpression of FGF21 suppresses the intake of both sugar and non-caloric sweeteners. FGF21 does not affect chorda tympani nerve responses to sweet tastants, instead reducing sweet-seeking behavior and meal size via neurons in the hypothalamus. This liver-to-brain hormonal axis likely represents a negative feedback loop as hepatic FGF21 production is elevated by sucrose ingestion. We conclude that the liver functions to regulate macronutrient-specific intake by producing an endocrine satiety signal that acts centrally to suppress the intake of “sweets.” FGF21 Mediates Endocrine Control of Simple Sugar Intake and Sweet Taste Preference by the Liver. Potthoff et al 2015.

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