Biology subjects

Zemer, A.

Publications and source records attributed to Zemer, A..

4 recordsLinked to original sources

bioRxiv2026

Time-restricted feeding corrects aggravation of glucose intolerance and circadian disruption induced by weight cycling in obese young mice

Weight cycling (WC), defined as weight gain, loss, and regain, is common in obesity, but its metabolic consequences remain unclear. We tested whether WC-aggravated glucose intolerance in obesity is age-dependent and linked to circadian disruption. Young (7w) and mid-aged (12m) mice underwent a 15-week dietary intervention: Lean and Obese mice fed normal chow (NC) and high-fat diet (HFD) throughout, respectively. WC mice undergone HFD-induced weight gain, NC-induced weight loss, and a second HFD-induced weight regain. Late-onset obese (LO) mice ate HFD only paralleling weight regain of WC. In young, but not mid-aged mice, prior obesity accelerated weight regain upon HFD re-exposure, and aggravated glucose intolerance beyond that observed in Obese mice. This occurred without a worse adipose inflammatory profile. Rather, WC young mice exhibited blunting of light/dark-phase oscillation of feeding and energy metabolism, adipose and hepatic core clock gene oscillation, and increased hepatic expression of clock and gluconeogenic genes during the inactive phase. Restricting food availability to the active phase did not alter final weight regain, but improved glucose tolerance selectively in WC mice, normalized hepatic gluconeogenic and clock-genes expression in both liver and adipose tissue. These findings identify circadian disruption as a modifiable mediator of the adverse metabolic impact of WC in young-adulthood obesity. HighlightsO_LIWeight cycling is common in obesity, but whether it worsens metabolic dysfunction beyond persistent obesity remains unclear. C_LIO_LIWe asked whether weight cycling aggravates glucose intolerance in an age-dependent manner and whether circadian disruption contributes to this effect. C_LIO_LIIn young, but not mid-aged mice, weight cycling accelerated weight regain and worsened glucose intolerance, accompanied by blunted diurnal oscillation of behavioral parameters and core clock gene expression, without exaggerated adipose inflammation. C_LIO_LIActive-phase time-restricted feeding improved WC-induced aggravated glucose tolerance and circadian oscillation, identifying circadian disruption as a modifiable mechanism linking weight cycling adverse metabolic outcomes in young-adulthood obesity. C_LI

biochemistry↗

bioRxiv2025

Weight cycling-induced hypothalamic and metabolic tissue immune remodeling is uncoupled from metabolic dysfunctions

BackgroundObesity-induced insulin resistance is associated with white adipose tissue (WAT) and liver inflammation, which are both mitigated by weight loss. However, most individuals undergoing weight loss will regain lost weight, resulting in weight cycling (WC), which may exacerbate metabolic dysfunctions. Here, we studied the immunometabolic impact of WC in mice. MethodsC57BL/6J mice were exposed to two cycles of weight gain and weight loss by alternating between low (LFD) and high-fat diet (HFD) feeding. Animals were sacrificed when WC mice were weight stable for 10 weeks upon weight loss (WC-lean) and after a subsequent exposure to weight regain for 10 weeks (WC-obese), and compared to mice persistently fed LFD (LFD-lean) or HFD (HFD-obese). ResultsBody weight stabilized at a higher level in WC-lean mice after two weight gain/loss cycles compared to LFD-lean controls. While insulin resistance, metabolic tissue inflammation, and hepatic steatosis normalized between the two groups of lean mice, WC-lean mice exhibited features of WAT dysfunction. In the hypothalamus, inflammatory microglia were less abundant in WC-lean mice compared to LFD-lean mice, but mean individual microglial cell volume was larger. WC-obese mice stabilized at slightly lower weight compared with HFD-obese controls. Intriguingly, WC-obese mice exhibited increased WAT macrophages and reduced WAT and liver effector T cells compared to HFD-obese mice, whereas energy intake, body composition, whole-body insulin resistance and hepatic steatosis were similar. ConclusionsOur results suggest that WC in mice differently impacts animals in the weight-stable lean and obese states. WC-lean mice display features of a novel body weight settling point, associated with hypothalamic inflammatory changes. However, metabolic dysfunctions were uncoupled from WC-induced metabolic tissue inflammation in WC-obese mice.

immunology↗

bioRxiv2025

Mid-aged mice rapidly normalize dysglycemia but aggravate obesity-induced hypothalamic and microglial changes upon dietary obesity reversal

ObjectiveObesity-induced-dysglycemia and hypothalamic-microgliosis coincide, but whether they remain linked upon obesity reversal, and what is the effect of age, remain unclear. Here we hypothesized that rapid normalization of dysglycemia upon obesity-reversal remains linked to microgliosis resolution, but differs between young and mid-aged mice. MethodsYoung (7w) and mid-aged (1y) mice were fed normal chow (NC) or high-fat diet (HFD,8w), then switched to NC (Rev,2w). ResultsCompared to young mice, NC-fed mid-aged mice were heavier and weight-stable, gained weight with HFD comparably, and lost less weight in Rev. HFD-induced dysglycemia was less severe in mid-aged compared to young mice, but similarly normalized by obesity-reversal. However, whole-hypothalamus RNA sequencing revealed 2,419 differentially expressed genes (DEGs) in mid-aged mice, [~]4-times more than in young mice, and in both age-groups [~]80% of DEGs obesity-induced changes were aggravated in Rev. Furthermore, compared with young mice, middle-aged mice showed greater obesity-induced microglial cyto-morphological changes in the arcuate nucleus (ARC), which associated with increased p-NF{kappa}B-(p-p65) nuclear staining. Only in middle-aged mice obesity-induced microglial changes were aggravated by obesity reversal, with cell volume correlating (Rho({rho})=0.691, p=0.001) with adipose tissue crown-like-structures. ConclusionsIn conclusion, rapid dysglycemia normalization is uncoupled to the resolution of hypothalamic microgliosis, more-so in mid-age.

cell biology↗

bioRxiv2024

CD4 T Cells Acquire Cytotoxic Properties to Modulate Cellular Senescence and Aging

Aging is characterized by the progressive deterioration of tissue structure and function, leading to increased vulnerability to diseases and, eventually, death. One prominent process in aging is the accumulation of senescent cells. Although the immune system has been recognized as crucial for the elimination of senescent cells, the associated mechanisms remain incompletely understood. Here we show that CD4 T cells differentiate into cytotoxic T lymphocytes (CTLs) in a senescent cell-rich environment and that a reduction in the senescent cell load, achieved using chemical senolytic drugs, was sufficient to halt this differentiation. We further demonstrate that eliminating CD4 CTLs in the context of late aging by selectively deleting the Eomes transcription factor in CD4 T cells resulted in the increased accumulation of senescent cells, profound physical deterioration, and a decreased life span. In liver cirrhosis, a model of localized chronic inflammation, CD4 CTL elimination increased the senescent load and worsened the disease. Collectively, our findings demonstrate the fundamental role of CD4 CTLs in modulating tissue senescence and unveil a new aspect of age-related T-cell biology implicated in disease susceptibility and longevity.

immunology↗