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The S100A8/A9 complex promotes food intake and prevents adipose tissue loss during cancer cachexia in mice

ABSTRACT: Cancer cachexia is a wasting syndrome characterized by reduced food intake, lean and fat tissue loss. Consistent with previous work we found in mice that cancer cachexia involved a reduction in host fat and lean tissue mass (particularly muscle), the latter balanced by tumor growth. 15N tracing experiments showed the tumor gets protein (nitrogen) from both food intake and breakdown of the host tissues. The absence of a change in total energy expenditure was due to metabolic compensation between the tumor, brown adipose tissue (BAT), and other tissues. We demonstrated this also in human cancer patients. The decrease in leptin caused by fat loss did not drive an increase in food intake or a reduction in total energy expenditure. We show that S100A8/A9 and C3 in the hypothalamus play a key role in the reduction of food intake and fat mass during cancer cachexia. Peripheral administration of S100A8/A9 inhibitors and hypothalamic knockdown of C3 significantly increased food intake and partially rescued fat and lean tissue loss.

ORGANISM(S): Mus musculus

PROVIDER: GSE304726 | GEO | 2026/09/30

REPOSITORIES: GEO

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Project description:Dietary protein restriction has been shown to increase energy expenditure and to improve insulin sensitivity in mice, but it is unknown whether humans exhibit similar phenotype to a prolonged eucaloric protein-restricted diet that meet daily protein minimum requirements. We hypothesize that a protein-restricted diet would necessitate an increase in energy intake in order to maintain body weight in healthy, lean men. We designed an overall amino acid diluted diet meeting the requirement for daily protein intake and essential amino acids. Healthy, young, lean men adhered to a protein-restricted, high-carbohydrate diet (LPHC: protein 9E%, 70E% carbohydrate, and 21E% fat) or a protein-restricted, high-fat diet (LPHF: 9E% protein, 50E% fat, and 40E% carbohydrate) for 5 weeks, followed by another 5 weeks on a higher, standard protein diet (HPD: 18E% protein), reflecting their habitual diet. The diets were eucaloric, and energy provision was adjusted to maintain body weight throughout the interventions. In addition, wild type (WT), and FGF21 knockout mice were also fed LPHC, LPHF diets, or a standard higher diet (HPD) for a total of 10 weeks. Our results showed that prolonged eucaloric LPHC and LPHF diets necessitated a daily increase of 20-21% (2.5 MJ) in food intake to maintain body weight compared to pre-intervention in healthy, lean men. Additionally, fasting plasma FGF21 levels increased from 90±125 pg/ml and 78±34 pg/ml to 257±99 pg/ml and 160±52 pg/ml at the end of the LPHC and LPHF, respectively. Furthermore, proteomic analysis revealed adaptations in the respiratory chain in human adipose tissue after 5-week protein-restricted diets. This was found to be dependent on FGF21 in mice, indicating increased energy utilization through alternative UCP1-independent futile cycle pathways likely mediated by FGF21. Moreover, whole-body insulin sensitivity, measured by a hyperinsulinemic-euglycemic clamp, was increased by 16% after the LPHC intervention while maintained after the LPHF intervention, despite the high fat intake. These findings suggest that a protein-restricted diet could serve as a promising approach to prevent weight gain and comorbidities associated with obesity.

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The S100A8/A9 complex promotes food intake and prevents adipose tissue loss during cancer cachexia in mice

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