Partial Body Mass Regain Following Caloric Restriction Reduces Lipid Utilization and Alters the Hepatic Lipidome Associated with HDL-Dysfunction During Metabolic Syndrome

Metabolic dysfunction-associated fatty liver disease (MAFLD) affects 38% of the global population and 50.7% of obese individuals. MAFLD is a primary outcome of metabolic syndrome (MetS) which is defined as three or more conditions: 1) abdominal obesity, 2) hypertension, 3) dyslipidemia, 4) glucose intolerance with or without insulin resistance, and 5) proinflammatory or prothrombotic state. Currently, there is no FDA treatment for MAFLD, which necessitates non-pharmaceutical interventions such as caloric restriction (CR) diets that are unsustainable for the majority of obese individuals causing body mass regain. CR has been shown to improve the plasma lipidome and hepatic lipid metabolism. However, the effects of partial body mass regain on the hepatic lipidome and lipid metabolism after a CR during MetS-associated MAFLD have yet to be investigated. A cohort of 15-week-old Otsuka Long Evan Tokushima Fatty (OLETF) and lean-strain control Long Tokushima Evans Otsuka (LETO) rats, animals were fed a 50% CR diet (compared to their control) for 10 days and assigned to four groups: 1) LETO ad lib control (n=14), 2) LETO CR (n=14), 3) OLETF ad lib control (n=14), and 4) OLETF CR (n=14). After the CR period, 7 animals from each group were then refed at pre-CR levels for 7 days and assigned to four groups: 1) LETO ad lib control (n=7), 2) LETO partial body mass regain (LETO PR; n=7), 3) OLETF ad lib control (n=7), and 4) OLETF PR (n=7). Hepatic carnitine palmitoyltransferase 2 (CPT2) and acyl-CoA oxidase 1 (ACOX1) protein expression decreased (44%; 27%) by PR compared to CR in the OLETF animals. HDL levels were greater (47%; p=0.007) in OLETF PR and LDL:HDL ratio (23%; p=0.01) was lower compared to OLETF CR. The lipidomics data demonstrated that PR primarily increased the fold-change of phosphatidylcholine and lysophosphatidylcholine compared to CR in the OLETF strain. Interestingly, the insulin area under the curve (11; ρ<-0.8 or ρ>0.8) and white adipose tissue (8; ρ<-0.8 or ρ>0.8) had the most lipid category correlations compared to body mass changes. The changes in the hepatic lipidome and the elevated HDL levels are similar to those seen during HDL dysfunction. Thus, these data indicate a potential correlation between HDL dysfunction and MetS-associated MAFLD progression during body mass regain. EJ: GRISE Bio-I-STeP 5T32GM141862-02 and AHA 23DIVSUP1066372MC: UC MEXUS-CONACY T440553 and the National Institute on Minority Health and Health Disparities 9T37-MD001480 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.