Dietary Naringenin Preserves Insulin Sensitivity and Grip Strength and Attenuates Inflammation but Accelerates Weight Loss in a Mouse Model of Cancer Cachexia

Abstract

Scope Cancer cachexia is characterized by the loss of skeletal muscle resulting in functional impairment, reduced quality of life and mortality. Naringenin, a flavonoid found in citrus fruits, improves insulin sensitivity and reduces inflammation and tumor growth in preclinical models. Therefore, the study hypothesizes that dietary supplementation of naringenin will improve insulin sensitivity, decrease inflammation, slow body weight loss, and delay tumor growth in a mouse model of cancer cachexia. Methods and Results Mice are fed 2 wt% dietary naringenin before and during initiation of cancer cachexia using inoculated adenocarcinoma‐26 cells (C‐26). Food intake, body weight, body composition, muscle function, insulin tolerance, and inflammatory status are assessed. Although naringenin‐fed tumor‐bearing mice exhibit reductions in body weight and food intake earlier than control diet‐fed tumor‐bearing mice, dietary naringenin is protective against loss of muscle strength, and attenuates the onset of insulin resistance and markers of inflammation. Conclusions Dietary supplementation of naringenin improves multiple aspects of metabolic disturbance and inflammation during cancer cachexia progression in [C‐26 tumor‐bearing] mice. However, the acceleration of anorexia and weight loss is also observed. These findings emphasize the link between inflammation and insulin resistance as a basis for understanding their roles in the pathogenesis of cancer cachexia.

Network pharmacology and molecular docking analysis reveal insights into the molecular mechanism of shiliao decoction in the treatment of cancer-associated malnutrition

“…For example, luteolin has been found to reduce cancer-induced skeletal muscle atrophy in a Lewis lung cancer mouse model by a mechanism that inhibits TNF-α and IL-6 directly and can suppress inflammation levels to treat cachexia by reducing NF-κB activation at the transcriptional and translational level ( 34 ). A 2021 study using mice with C26 cells found that naringenin prevented the loss of muscle strength and decreased levels of insulin resistance and inflammation ( 35 ). Many reports have demonstrated that kaempferol is a safe and effective natural dietary anti-inflammatory agent, and the poor bioavailability of kaempferol has also been addressed by nanotechnology ( 36 ).…”

New insights of active constituents from herbs and nutraceuticals and their mechanisms in obesity-induced insulin resistance

“…Naringenin is a Citrus flavonoid with remarkable therapeutic effects on hyperlipemia, obesity and IR. A previous study demonstrated that naringenin restored the grip strength, increased the insulin sensitivity, and inhibited inflammation in C-26 tumor-bearing mice (Snoke et al, 2021). As shown in a case study on a diabetic woman, naringenin supplementation could reduce body weight, insulin content and HOMA-IR, and further in vitro experiment demonstrated that naringenin might act via regulating PPARα and PPARγ expression in human subcutaneous adipose-derived stem cells (Murugesan, Woodard, Ramaraju, Greenway, Coulter & Rebello, 2020).…”

Therapeutic Potential of Bioactive Flavonoids from Citrus Fruit Peels toward Obesity and Diabetes Mellitus

“…Using HFD-fed obese ovariectomized mice, Ke et al discovered that naringenin administration placed beneficial effects on metabolic health and tumorigenesis of obesityrelated postmenopausal breast cancer via activation of AMPK signaling and induction of cell death in tumor cells [64]. Similarly, Snoke et al also found that in a colon-26 cancer cachexia mouse model, naringenin administration improved insulin sensitivity while suppressed inflammation and adenocarcinoma growth [65].…”

“…Colon-26 cancer cachexia mice [65] Ang II, AT1 receptor, gp91phox, p-NF-κB [69], ERs [30], iNOS, MAPKs, NF-kB, TNF-α, p50, MCP-1 [70] 3T3-L1 [30], 3T3-L1 and RAW264 macrophages coculture [70] HFD-fed SD rats [69], HFD-fed obese mice [30] Flavonoids Amelioration of hyperglycemia, hypercholesterolemia and NAFLD, Amelioration of metabolic syndrome adiponectin, MCP-1, resistin, and caspase 3 [73], AMPK, ACC, GSK3β, SREBP-2, HMGCR [45], AMPK, ACC [76], LDL, IL-1β, IL-6 [83], ABCA1, ABCG1, PPARγ, LXRα [77], AdipoR1, gp91 [79], adiponectin, MCP-1, IL-6, PPARγ, GLUT4, GLUT1, Akt [78,80], C/EBPβ, PPARδ, PPARα, PGC-1α, UCP1, 3T3-L1 [72][73][74][75], PAtreated HepG2 [45],…”