Raised FGF-21 and Triglycerides Accompany Increased Energy Intake Driven by Protein Leverage in Lean, Healthy Individuals: A Randomised Trial

Abstract

A dominant appetite for protein drives increased energy intake in humans when the proportion of protein in the diet is reduced down to approximately 10% of total energy. Compensatory feeding for protein is apparent over a 1–2 d period but the mechanisms driving this regulation are not fully understood. Fibroblast growth factor-21 (FGF-21) has been identified as a candidate protein signal as levels increase in the circulation when dietary protein is low. The aim of this randomised controlled trial was to assess whether changes in percent dietary protein over a 4 d ad libitum experimental period in lean, healthy participants influenced energy intake, metabolic health, circulating FGF-21 and appetite regulating hormones including ghrelin, glucagon like peptide-1 and cholecystokinin. Twenty-two lean, healthy participants were fed ad libitum diets containing 10, 15 and 25% protein, over three, 4 d controlled, in-house experimental periods. Reduced dietary protein intake from 25% to 10% over a period of 4 d was associated with 14% increased energy intake (p = 0.02) as previously reported, and a 6-fold increase in fasting circulating plasma FGF-21 levels (p<0.0001), a 1.5-fold increase in serum triglycerides (p<0.0001), and a 0.9-fold decrease in serum total cholesterol (p = 0.02). Serum HDL cholesterol was reduced with a reduction in dietary protein from 15% to 10% (p = 0.01) over 4 d but not from 25% to 10% (p = 0.1) and the change from baseline was not different between diets. Plasma fasting insulin levels following the 4 d study period were significantly lower following the 25% ad libitum study period compared to the 15% protein period (p = 0.014) but not the 10% protein period (p = 0.2). Variability in interstitial glucose during each study period increased with a decrease in dietary protein from 25% to 15% and 10% (p = 0.001 and p = 0.04, respectively). Ghrelin, glucagon-like peptide-1 and cholecystokinin were unchanged. Increases in energy intake, plasma FGF-21 and serum triglycerides were associated with reductions in percent dietary protein from 25% to 10% energy over a 4 d ad libitum in-house feeding period and may be important in regulation of dietary protein intake.Trial RegistrationAustralia New Zealand Clinical Trials Registry ACTRN12616000144415

Fibroblast growth factor 21: an endocrine inhibitor of sugar and alcohol appetite

“…Diets low in protein have also been shown to elevate hepatic and plasma FGF21 levels in rodents and humans (Laeger et al 2014;Ozaki et al 2015;Gosby et al 2016;Pezeshki et al 2016;Pérez-Martí et al 2017). However, when decreasing the proportion of the diet derived from one nutrient in an isocaloric paradigm the proportion of another must increase and some studies are complicated by their concomitant higher sugar and carbohydrate content.…”

Dietary Fat, but Not Protein or Carbohydrate, Regulates Energy Intake and Causes Adiposity in Mice

“…Applications of this approach to many species suggest that animals may eat food primarily to achieve a target intake of protein (Felton et al, 2009;Hawley et al, 2016;Raubenheimer and Simpson, 1997), which may be driven in part by fibroblast growth factor (FGF) signaling (Gosby et al, 2016). This contrasts the classical interpretation that food intake serves primarily to match energy demands.…”

“…Other patterns are possible and would require more complex fitting procedures. The leveraging of total intake by protein has been widely supported by empirical observations in a wide range of animals from insects to non-human primates (Felton et al, 2009;Gosby et al, 2016;Hawley et al, 2016;Raubenheimer and Simpson, 1997) and humans (Gosby et al, 2011;Martens et al, 2013;Martinez-Cordero et al, 2012;Simpson et al, 2003), although the percentage contribution of protein leverage to total intake has generally not been quantified as explicitly as indicated by the above approach. Nevertheless, protein leverage is increasingly being used to understand aspects of comparative feeding biology and the human obesity epidemic (Bekelman et al, 2017).…”

Low‐Protein Diets with Fixed Carbohydrate Content Promote Hyperphagia and Sympathetically Mediated Increase in Energy Expenditure

“…The protein leverage hypothesis postulates that dietary protein restriction elicits a compensatory increase in calorie intake (hyperphagia) to achieve protein requirements . The authors and others reported that mild protein restriction increases caloric intake in rodents and in some, but not in all human studies . Most studies assessing the effects of protein restriction on energy balance formulated isocaloric diets by substituting protein with carbohydrate, while keeping fat concentration constant;; whether the hyperphagic and metabolic responses to protein restriction are due to a reciprocal increase in carbohydrate content is largely unknown.…”