**4.1 Mechanism**

Overnutrition increases the supply of glucose and fat that can feed into metabolic reprogramming to fuel cancer cell proliferation. In addition, glycolysis has been shown to be enhanced in cancer cells of obese individuals. As obesity is often associated with metabolic syndrome (MS) and diabetes, characterized by hyperglycemia and/or hypertriglyceridemia, an abundance of circulating nutrients are available for tumor development, even between feeding periods [45]. Autophagy, the process whereby cancer cells digest and recycle their cellular contents during periods of low nutrient availability, can provide cancer cells with lipids, amino acids, and nucleotides required for proliferation [46]. Obesity has been shown to induce autophagy, particularly in adipocytes [45]. These obesity-associated metabolic adaptations facilitate the development of cancer traits that include insensitivity to anti-growth signals, resistance to cell death, and deregulation of cellular energetics [47]. Hence, interactions between cancer cell energetics and systemic metabolism highlight unique therapeutic strategies and interventions, particularly among obese individuals, as cancer cells may be more sensitive to metabolic interference, having already committed to metabolic reprogramming [45].

In addition, obesity and MS are associated with abnormalities in insulin signaling, growth factor signaling, and glucose metabolism [48]. One growth factor implicated in cancer risk and progression is insulin-like growth factor (IGF)-1. Hyperglycemia and hyperinsulinemia, diagnostic criteria of MS, increase IGF-1 production and bioavailability. Furthermore, hyperglycemia suppresses IGF-1 binding protein synthesis, while hyperinsulinemia promotes expression of growth hormone receptor and subsequent IGF-1 synthesis [48]. Growth and survival functions of IGF-1 give it the potential to have an impact on many characteristics of cancer, including sustained proliferative signaling, insensitivity to anti-growth signals, induction of angiogenesis, and metastatic potential [49]. As a result, elevated IGF-1 has been established as a risk factor for CRC [45].

Higher body fatness is associated with increased insulin levels, which can promote cell growth and inhibit apoptosis and has been linked to a greater risk of CRC in humans [50, 51] and in experimental studies [52]. Body fatness also stimulates the body's inflammatory response, which can promote CRC development [53, 54]. Overall, there are convincing mechanistic data supporting a link between body fatness and CRC [8].
