The scientific literature broadly supports the view that the simple "calories in, calories out" framing omits significant biological complexity—including adaptive thermogenesis, hormonal regulation of appetite and metabolism, and variable metabolic efficiency of different macronutrients. However, energy balance remains a valid physical constraint on weight change; the claim is accurate in calling CICO an oversimplification of metabolic processes, but should not be read as suggesting energy balance is biologically false.

Strong peer-reviewed evidence — including randomized controlled trials and meta-analyses — supports the claim that reducing body fat decreases inflammatory markers such as CRP, IL-6, and TNF-α in humans. The link between improved diet quality and lower inflammation is also well-supported, though much of that evidence is observational and harder to separate from concurrent weight loss. The claim's broad phrasing slightly overstates universality, as effects vary by population, degree of fat loss, and specific biomarker measured.