Cerebrospinal Fluid Fatty Acids, Hypothalamic Inflammation, and Weight Loss in Human Obesity: A Longitudinal Study

Preclinical studies show that dietary or central administration of monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) can reduce food intake, enhance energy expenditure, and attenuate hypothalamic inflammation (HI), whereas saturated fatty acids (SFAs) promote weight gain, HI, and neuronal injury. However, whether hypothalamic exposure to different fatty acids similarly influences HI and body weight in humans remains unclear. In this longitudinal study, we compared cerebrospinal fluid (CSF) free fatty acid (FFA) profiles between 19 normal-weight control participants and 44 individuals with obesity, both at baseline and 1 year after bariatric surgery (BS). We also examined associations between CSF FFA composition, MRI-based markers of HI (i.e., increased hypothalamic mean diffusivity [MD] and volume), and postoperative weight loss. At baseline, individuals with obesity had similar CSF concentrations of total FFA, SFA, and MUFA compared with control participants but significantly lower PUFA levels, mainly due to reduced docosahexaenoic acid (DHA) levels. BS did not substantially alter CSF FFA profiles. Lower baseline CSF DHA levels were associated with higher hypothalamic MD and independently predicted less weight loss at 1 year. Postoperative increases in CSF DHA levels correlated with reductions in hypothalamic MD. These findings suggest brain DHA level may influence hypothalamic microstructure and contribute to body weight regulation in human obesity. Article Highlights Whether hypothalamic exposure to free fatty acid (FFA) species contributes to obesity and hypothalamic inflammation (HI) in humans is not yet defined. We compared cerebrospinal fluid FFA profiles between normal-weight control participants and individuals with obesity, before and after bariatric surgery (BS), and examined their associations with postoperative weight trajectories and neuroimaging biomarkers of HI. Individuals with obesity had reduced cerebrospinal fluid levels of docosahexaenoic acid (DHA) before and after BS. Lower cerebrospinal fluid DHA levels correlated with biomarkers of HI and were independently associated with less weight loss after BS. The findings highlight the potential of DHA in modulating hypothalamic function.