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

Abstract

Scope: Dietary protein restriction elicits hyperphagia and increases energy expenditure; however, less is known of whether these responses are a consequence of increasing carbohydrate content. The effects of protein-diluted diets with fixed carbohydrate content on energy balance, hormones, and key markers of protein sensing and thermogenesis in tissues are determined. Methods and results: Obesity-prone rats (n = 13-16 per group) are randomized to diets containing fixed carbohydrate (52% calories) and varying protein concentrations: 15% (control), 10% (mild protein restriction), 5% (moderate protein restriction) or 1% (severe protein restriction) protein calories, or protein-matched to 5% protein, for 21 days. Propranolol and ondansetron are administered to interrogate the roles of sympathetic and serotonergic systems, respectively, in diet-induced changes in energy expenditure. It is found that mild-to-moderate protein restriction promotes transient hyperphagia, whereas severe protein restriction induces hypophagia, with alterations in meal patterns. Protein restriction enhances energy expenditure that is partly attenuated by propranolol, but not ondansetron. Moderate to severe protein restriction decreases gains in body weight, lean and fat mass, decreased postprandial glucose and leptin, but increased fibroblast growth factor-21 concentrations. Protein-matching retains lean mass suggesting that intake of dietary protein, but not calories, is important for preserving lean mass. Notably, protein restriction increases the protein and/or transcript abundance of key amino acid sensing molecules in liver and intestine (PERK, eIF2α, ATF2, CHOP, 4EBP1, FGF21), and upregulated thermogenic markers (β2AR, Klotho, HADH, UCP-1) in brown adipose tissue. Conclusion: Low-protein diets promote hyperphagia and sympathetically mediated increase in energy expenditure, prevent gains in tissue reserves, and concurrently upregulate hepatic and intestinal amino acid sensing intermediaries and thermogenic markers in brown adipose tissue.

Low Protein Diets and Energy Balance: Mechanisms of Action on Energy Intake and Expenditure

“…Accumulating evidence indicates that moderate protein restriction in rodents (5–8% protein kcal) stimulates FGF21 secretion from the liver which acts on β-klotho receptors in the brain to promote hyperphagia ( 34 – 36 ) ( Figure 1 ). We have also shown that such hyperphagic responses to protein dilution are a consequence of increased meal size in rodents ( 31 ). The hyperphagic responses to moderate protein dilution are also associated with reduction in circulating concentrations of leptin and IGF-1, increased plasma ghrelin, and upregulation of orexigenic neuropeptide Y transcripts in the rodent hypothalamus ( 27 , 31 , 37 , 38 ).…”

“…Consistent with these studies that were mostly conducted in vitro and with amino acids, we ( 27 ) and others ( 28 – 30 ) showed that a similar pathway for sensing dietary protein deficiency also operates in the liver to upregulate hepatic FGF21 expression and secretion. Interestingly, we found that similar amino acid sensing pathways were also upregulated in the duodenum ( 31 ) suggesting that the intestine may detect protein deficiency prior to the liver, and/or that the intestinal sensing may serve to amplify the hepatic response to protein restriction. Independent of sensing by gut-associated tissues, amino acid deprivation causes a rapid anorexic response that is triggered by GCN2 signaling in the piriform cortex ( 32 , 33 ).…”

“…The hyperphagic responses to moderate protein dilution are also associated with reduction in circulating concentrations of leptin and IGF-1, increased plasma ghrelin, and upregulation of orexigenic neuropeptide Y transcripts in the rodent hypothalamus ( 27 , 31 , 37 , 38 ). Although the role of anorexigenic lower gut peptides such as peptide YY and glucagon-like peptide-1 (GLP-1) in high-protein induced hypophagia is well-documented in rodents ( 39 – 41 ) and humans ( 42 ), we were unable to detect a graded insufficiency in circulating concentrations of these and other anorectic gut hormones (e.g., gastric inhibitory polypeptide and amylin) in rats ( 27 , 31 ) that might explain the hyperphagia with protein dilution. It is unknown whether sensitivity to hypophagic effects of these satiety hormones is impaired with dietary protein restriction.…”

“…However, birds fed with low protein diets were found to have a higher occurrence of GLP-1-immunoreactive cells in the ileum ( 43 ). Though the hyperphagic responses to protein dilution are consistently observed in a no-choice condition ( 27 – 31 , 36 ), when protein restricted rodents are given a choice of macronutrients, they tend to prefer protein ( 8 , 34 , 44 ) with reduced preference for carbohydrates ( 45 , 46 ). Similarly, in humans, the fMRI BOLD responses to food cues were greater in reward areas such as orbitofrontal cortex and striatum under low protein conditions ( 7 ).…”

Protein, amino acids and obesity treatment

“…Low protein intake was positively associated with metabolically healthy obesity in women [ 8 ]. In rats, mild (10% of total energy intake (TEI)) to moderate protein restriction (5% of TEI) is associated with hyperphagia and increases energy expenditure through activation of the sympathetic system [ 9 ]. Additionally, authors found similar lean mass in the group of rats with a 10% protein diet matched in protein intake to the 5% protein group, suggesting that the intake of dietary protein, but not calorie intake is necessary to preserve lean body mass.…”