Excess adiposity, a worldwide-growing pathological condition, is now recognized as a main risk factor for most chronic diseases including colorectal cancer (CRC). Obese subjects show an increased cancer incidence with obesity representing an important indicator of survival, prognosis, recurrence and response to therapy. A low-grade chronic inflammation of metabolically active tissues including the adipose tissue (AT), defined as meta-inflammation, is a main feature of obesity. Fatty acids (FA), the main AT components, are important modulators of inflammation, and the type of FA stored in AT critically affects tissue functions. Their profile within AT mirrors FA dietary intake but also depends on a metabolic control. Obesity, changes in the habitual diet, weight loss or pathological conditions like CRC influence FA profile of AT pointing to these molecules as important actors in AT dysfunction and meta-inflammation, that characterize metabolic diseases and may favor cancer development. Worth of note, diet is receiving growing attention as a main determinant in cancer prevention due to its capacity to modulate immune response and inflammation. Alterations in the balance between different families of FA may contribute to generate a pro-inflammatory profile with deleterious effects on metabolic and immune homeostasis at both local and systemic levels. This review focuses on FA as regulators of human AT inflammation discussing the role of obesity-, diet-, and weight loss-associated changes in FA profile in this process. The relevance of FA composition of AT in linking diet, obesity and CRC will be also reviewed.