Rapid metabolic improvement induced by early obesity reversal is associated with sustained hypothalamic inflammation

Alon Zemer ^1,2 Yulia Haim ¹ Yair Pincu ^1,3 Alexandra Tsitrina ¹ Omer Berner ² Alon Monsonego ² Assaf Rudich ^1,4

¹Department of Clinical Biochemistry and Pharmacology, Ben Gurion University, Israel
²The Shraga Segal Department of Microbiology, Immunology, and Genetics, Ben Gurion University, Israel
³Department of Health and Exercise Science, University of Oklahoma, USA
⁴The National Institute of Biotechnology in the Negev, Ben Gurion University, Israel

Introduction: Obesity induces meta-inflammation- a low-grade inflammatory state engaging “metabolic organs” and in the hypothalamus, where inflammation is implicated in obesity-related metabolic dys-regulation. We previously demonstrated in young mice that dietary switch from obesogenic to normal-chow (NC) diet rapidly and nearly-fully reverses obesity-induced dys-glycemia. Here we investigated the corresponding reversal of hypothalamic inflammation, and its interplay with aging.

Methods: C57BL/6 mice (7-weeks, or 1-year old) were fed either NC or a 60% high-fat diet (HFD) for 10-weeks. Obesity-reversal mice were switched back to NC for the last 2 weeks (‘Reverse’). At the end of the 10-weeks intervention, hypothalamic inflammation was assessed by RT-PCR, confocal analysis, and bulk-RNA sequencing.

Results: Young and older ‘Reverse` mice lost 66±8.2% and 52±10.3%, respectively, of the excess body weight gained during 10w-HFD(p=NS). Older mice exhibited fasting hyperglycemia(p<0.05) compared to the corresponding young mice in all dietary groups, but early obesity reversal completely normalized HFD-induced hyperglycemia in both age groups. Surprisingly, in the young mice, gene expression analysis revealed increased levels of IL1b mRNA in hypothalami of Reverse mice, compared to both other groups. Immunofluorescence analysis of hypothalami from both young and older mice for microglia (Iba1, CD68) and astrocytes (GFAP) reveled significant microgliosis in HFD compared to the NC group. Unexpectedly, this microgliosis was only minimally reduced in the Reverse group.

Conclusion: Despite near-normalized glycemia, only minor reversibility was documented in the hypothalamus during early obesity reversal. These results beg further study to unveil hypothalamic inflammation’s role in rapidly restoring glycemia during early obesity reversal.