<b>Cerebrospinal fluid fatty acids, hypothalamic inflammation, and weight loss in human obesity: a longitudinal study.</b>

<p dir="ltr">Preclinical studies show that dietary or central administration of monounsaturated (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.</p><p dir="ltr">In this longitudinal study, we compared cerebrospinal fluid (CSF) free fatty acid (FFA) profiles between nineteen normal-weight controls and forty-four individuals with obesity, both at baseline and one year after bariatric surgery (BS). We also examined associations between CSF-FFA composition, MRI-based markers of HI—increased hypothalamic mean diffusivity (MD) and volume—and postoperative weight loss.</p><p dir="ltr">At baseline, individuals with obesity had similar CSF concentrations of total FFA, SFA, and MUFA compared to controls, but significantly lower PUFA levels, mainly due to reduced docosahexaenoic acid (DHA). 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 one year. Postoperative increases in CSF-DHA correlated with reductions in hypothalamic MD.</p><p dir="ltr">These findings suggest that brain DHA may influence hypothalamic microstructure and contribute to body weight regulation in human obesity.</p>