Biology subjects

Bartke, A.

Publications and source records attributed to Bartke, A..

9 recordsLinked to original sources

bioRxiv2025

Surgical Removal of Visceral Adipose Tissue has Therapeutic Benefit in Male APPNL-F Mice

PurposeVisceral white adipose tissue (vWAT) accumulation causes systemic inflammation, insulin resistance, metabolic syndrome, and senescent cell accumulation that are risk factors for Alzheimers disease (AD). Visceral fat removal (VFR) improves metabolism and reduces pro-inflammatory cytokines. We hypothesized that VFR removal in AD mice would improve metabolism and cognition. MethodsMale and female APPNL-F mice underwent sham or vWAT surgical resection (periovarian or epididymal and perirenal) at 4 (pre-symptomatic) and 16 (symptomatic) months of age to understand interventional and therapeutic effects, respectively. At 18 months of age, glucose metabolism and novel object recognition (NOR) memory were assayed followed by assessment of body composition and tissue-specific markers of metabolism, cell senescence, inflammation, or amyloid accumulation. ResultsMale and female APPNL-F mice showed distinct VFR responses. In pre-symptomatic males, increased vWAT lipolysis and hepatic lipogenesis led to ectopic liver lipid accumulation, with reduced adiponectin and leptin, elevated visfatin, and impaired glucose metabolism. Symptomatic males showed reduced vWAT lipogenesis, enhanced hepatic lipolysis, glycolysis, and glycogenesis, lowering liver lipids and improving insulin sensitivity. Only symptomatic males improved NOR, linked to elevated hippocampal learning and memory markers. Female vWAT reaccumulation was due to increased lipogenesis and lower lipolysis. Pre-symptomatic females had lower hepatic lipogenesis, while glycolysis and glycogenesis declined with disease progression. Hippocampal senescence and inflammation were elevated early in the disease that persisted symptomatically. ConclusionsSex-specific differences in glucose and lipid metabolism and lipid accumulation underlie the divergent responses to VFR in APPNL-F mice, with symptomatic males showing the only beneficial outcomes in metabolism and cognition. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/669175v2_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@6ec644org.highwire.dtl.DTLVardef@9ad821org.highwire.dtl.DTLVardef@1e37775org.highwire.dtl.DTLVardef@b7a558_HPS_FORMAT_FIGEXP M_FIG C_FIG Male and female APPNL-F mice exhibited distinct VFR responses to AD progression. In males, early disease stages were marked by vWAT lipolysis and hepatic lipid accumulation with metabolic dysfunction, while symptomatic stages showed a metabolic shift that improved insulin sensitivity and NOR performance. In contrast, females displayed progressive vWAT reaccumulation, reduced hepatic metabolism, and persistent hippocampal senescence and inflammation from early stages onward.

neuroscience↗

bioRxiv2025

Growth Hormone Excess Drives Liver Aging via increased Glycation stress

Growth hormone (GH) plays a crucial role in various physiological functions, with its secretion tightly regulated by complex endocrine mechanisms. Pathological conditions such as acromegaly or pituitary tumors result in elevated circulating GH levels, which have been implicated in a spectrum of metabolic disorders, potentially by regulating liver metabolism. In this study, we focused on the liver, a key organ in metabolic regulation and a primary target of GH, to investigate the impact of high circulating GH on liver metabolism. We used bovine GH overexpressing transgenic (bGH-Tg) mice to conduct a comprehensive transcriptomic analysis of hepatic tissues. The bGH-Tg mouse livers exhibit dysregulated fatty acid metabolism and heightened inflammatory responses. Notably, the transcriptomic profile of young bGH-Tg mouse livers resembled that of aged livers and displayed markers of increased cellular senescence. Furthermore, these mice exhibited a significant accumulation of advanced glycation end products (AGEs). Intervention with glycation-lowering compounds effectively reversed the insulin resistance and aberrant transcriptomic signatures in the liver that are associated with elevated GH levels. These findings underscore the potential therapeutic value of glycation-lowering agents in mitigating the deleterious effects of chronic GH overexpression. HighlightsO_LIOverexpression of bovine growth hormone impacts transcriptional changes in liver fat metabolism and inflammatory response in mice. C_LIO_LIHigh circulating growth hormone leads to transcriptional changes that suggest enhanced liver aging and induce cellular senescence. C_LIO_LIDetoxification pathways in bGH-Tg mice are inhibited, leading to the accumulation of Advanced Glycation End (AGE) products. C_LIO_LIGlycation-lowering compounds can mitigate pathologies associated with high GH levels. C_LI

physiology↗

bioRxiv2024

Lifespan of male and female APP/PS1 and APPNL-F/NL-F mouse models of Alzheimer's disease

Alzheimers disease (AD) disproportionately affects women, yet most preclinical research studies are male-centric. We performed lifespan analyses of male and female AD mouse models (APP/PS1 and APPNL-F/NL-F) and their shared genetic background control (C57BL/6). Survival curves support significant sex differences between within genotypes. Minimal longevity revealed increased age in male APP/PS1, and decreased age in APPNL-F/NL-F mice. Maximal longevity revealed an increased average age in males. Furthermore, median lifespan differed between sex and genotype. This study supports sexual dimorphic survival in two mouse models of AD, emphasizing the need to examine mechanisms and treatments in both sexes.

physiology↗

bioRxiv2024

Thermotherapy has Sexually Dimorphic Responses in APP/PS1 Mice

A thermoregulatory decline occurs with age due to changes in muscle mass, vasoconstriction, and metabolism that lowers core body temperature (Tc). Although lower Tc is a biomarker of successful aging, we have previously shown this worsens cognitive performance in the APP/PS1 mouse model of Alzheimers disease (AD) [1]. We hypothesized that elevating Tc with thermotherapy would improve metabolism and cognition in APP/PS1 mice. From 6-12 months of age, male and female APP/PS1 and C57BL/6 mice were chronically housed at 23 or 30{degrees}C. At 12 months of age, mice were assayed for insulin sensitivity, glucose tolerance, and spatial cognition. Plasma, hippocampal, and peripheral (adipose, hepatic, and skeletal muscle) samples were procured postmortem and tissue-specific markers of amyloid accumulation, metabolism, and inflammation were assayed. Chronic 30{degrees}C exposure increased Tc in all groups except female APP/PS1 mice. All mice receiving thermotherapy had either improved glucose tolerance or insulin sensitivity, but the underlying processes responsible for these effects varied across sexes. In males, glucose regulation was influenced predominantly by hormonal signaling in plasma and skeletal muscle glucose transporter 4 expression, whereas in females, this was modulated at the tissue level. Thermotherapy improved spatial navigation in male C57BL/6 and APP/PS1 mice, with the later attributed to reduced hippocampal soluble amyloid-{beta} (A{beta})42. Female APP/PS1 mice exhibited worse spatial memory recall after chronic thermotherapy. Together, the data highlights the metabolic benefits of passive thermotherapy, but future studies are needed to determine therapeutic benefits for those with AD.

neuroscience↗

bioRxiv2023

Senolytic Intervention Improves Cognition, Metabolism, and Adiposity in Female APPNL-F/NL-F Mice.

Senescent cells accumulate throughout the body and brain contributing to unhealthy aging and Alzheimers disease (AD). The APPNL-F/NL-F amyloidogenic AD mouse model exhibits increased markers of senescent cells and the senescence-associated secretory phenotype (SASP) in visceral white adipose tissue before plaque accumulation and cognitive decline. We hypothesized that senolytic intervention would alleviate cellular senescence thereby improving spatial memory in APPNL-F/NL-F mice. Thus, four month old male and female APPNL-F/NL-F mice were treated monthly with vehicle, 5 mg/kg Dasatinib + 50 mg/kg Quercetin, or 100 mg/kg Fisetin. Blood glucose levels, energy metabolism, spatial memory, amyloid burden, and senescent cell markers were assayed. Dasatinib + Quercetin treatment in female APPNL-F/NL-F mice increased oxygen consumption and energy expenditure resulting in decreased body mass. White adipose tissue mass was decreased along with senescence markers, SASP, blood glucose, and plasma insulin and triglycerides. Hippocampal senescence markers and SASP were reduced along with soluble and insoluble amyloid-{beta} (A{beta})42 and senescence associated-{beta}-gal activity leading to improved spatial memory. Fisetin had negligible effects on these measures in female APPNL-F/NL-F mice while neither senolytic intervention altered these parameters in the male mice. Considering women have a greater risk of dementia, identifying senotherapeutics appropriate for sex and disease stage is necessary for personalized medicine.

neuroscience↗

bioRxiv2022

Growth hormone receptor (GHR) in AgRP neurons regulatesthermogenesis in aged mice in a sex-specific manner

Evidence for hypothalamic regulation of energy homeostasis and thermoregulation in brown adipose tissue (BAT) during aging has been well recognized, yet the central molecular mediators involved in this process are poorly understood. The arcuate hypothalamus (ARC), orexigenic agouti-related peptide (AgRP) neurons control nutrient intake, energy homeostasis, and BAT thermogenesis. To determine the roles of growth hormone receptor (GHR) signaling in the AgRP neurons we used mice with the AgRP-specific GHR deletion (AgRP{Delta}GHR). We found that female AgRP{Delta}GHR mice were resistant to temperature adaptation, and their body core temperature remained significantly lower when held at 10{degrees}C, 22{degrees}C, or 30{degrees}C, compared to control mice. Low body core temperature in female AgRP{Delta}GHR mice has been associated with significant reductions in Ucp1 and Pgc1 expression in the BAT. Further, neuronal activity in AgRP in response to cold exposure was blunted in AgRP{Delta}GHR females, while the number of Fos+ AgRP neurons was increased in control females exposed to cold. Global transcriptome from BAT identified increased expression of genes related to immune responses and chemokine activity and decreased expression of genes involved in triglycerides synthesis and metabolic pathways in AgRP{Delta}GHR females. Importantly, these were the same genes that are downregulated by thermoneutrality in control mice but not in the AgRP{Delta}GHR animals. Collectively, these data demonstrate a novel circuit of thermal regulation between the hypothalamic AgRP-GHR and BAT and provide insight into the brain systems that are critical for the thermogenic vitality of the elderly.

neuroscience↗

bioRxiv2021

Sexual dimorphic responses of C57BL/6 mice to Fisetin or Dasatinib and Quercetin cocktail oral treatment

Senolytic treatment in aged mice clears senescent cell burden leading to functional improvements. However, less is known regarding the effects of these compounds when administered prior to significant senescent cell accumulation. From 4-13 months of age, C57BL/6 male and female mice received monthly oral dosing of either 100 mg/kg Fisetin or a 5 mg/kg Dasatinib (D) plus 50 mg/kg Quercetin (Q) cocktail. During treatment, several aspects of healthy aging were assayed including glucose metabolism using an insulin and glucose tolerance test, cognitive performance using Morris water maze and novel object recognition, and energy metabolism using indirect calorimetry. Afterwards, mice were euthanized for plasma and tissue specific markers of senescence-associated secretory phenotype (SASP) and white adipose tissue accumulation (WAT). Sexually dimorphic treatment effects were observed. Fisetin treated male mice had reduced SASP, enhanced glucose and energy metabolism, improved cognitive performance, and increased mRNA expression of adiponectin receptor 1 and glucose transporter 4. D+Q treatment had minimal effects in male C57BL/6 mice, but was detrimental to females causing increased SASP expression along with accumulation of WAT depots. Reduced energy metabolism and cognitive performance were also noted. Fisetin treatment had no effect in female C57BL/6 mice potentially due to a slower rate of biological aging. In summary, the senolytic treatment in young adulthood, has beneficial, negligible, or detrimental effects in C57BL/6 mice dependent upon sex and treatment. These observations should serve as a note of caution in this rapidly evolving and expanding field of investigation. Graphical AbstractMale and female C57BL/6 mice were treated with once monthly oral doses of either Dasatinib (D) + Quercetin (Q) or Fisetin from 4-13 months of age. Females treated with D+Q had increased adiposity and SASP markers (red spheres) along with decreased metabolism (blue flame) and cognitive performance. Males treated with Fisetin had reduced SASP markers (blue spheres) as well as improved metabolism (red flame) and cognition. No effects were observed in females treated with Fisetin or males treated with D+Q. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/467509v2_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@1d7f450org.highwire.dtl.DTLVardef@e8b32forg.highwire.dtl.DTLVardef@14be597org.highwire.dtl.DTLVardef@1ce31af_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2020

DNA damage and macrophage infiltration in the ovaries of the long-lived GH deficient Ames Dwarf and the short-lived bGH transgenic mice

ObjectiveThe aim of the study was to evaluate the role of growth hormone (GH) in DNA damage, macrophage infiltration and the granulosa cells number of primordial and primary follicles. MethodsFor these experiments six groups of female mice were used. Four groups consisted of Ames dwarf (Prop-1df, df/df, n=12) and their normal littermates (N/df, n=12) mice, between sixteen and eighteen month-old, receiving GH (n=6 for df/df, and n=6 for N/df mice) or saline injections (n=6 for df/df, and n=6 for N/df mice). The other two groups consisted of ten to twelve-month-old bGH (n=6) and normal mice (N, n=6). Immunofluorescence for DNA damage (anti-{gamma}H2AX) and macrophage counting (anti-CD68) were performed. Granulosa cells of primordial and primary follicles were counted. ResultsFemale df/df mice had lower {gamma}H2AX foci intensity in in both oocytes and granulosa cells of primordial and primary follicles (p<0.05), indicating less DNA double strand breaks (DSBs). In addition, GH treatment increased DSBs in both df/df and N/df mice. Inversely, bGH mice had higher quantity of DSBs in both oocytes and granulosa cells of primordial and primary follicles (p<0.05). Df/df mice showed ovarian tissue with less macrophage infiltration than N/df mice (p<0.05) and GH treatment increased macrophage infiltration (p<0.05). On the other hand, bGH mice had ovarian tissue with more macrophage infiltration compared to normal mice (p<0.05). Df/df mice had less granulosa cells on primordial and primary follicles than N/df mice (p<0.05). GH treatment did not affect the granulosa cells number (p>0.05). However, bGH mice had an increased number of granulosa cells on primordial and primary follicles compared to normal mice (p<0.05). ConclusionThe current study points to the role of the GH/IGF-I axis in maintenance of oocyte DNA integrity and macrophage ovarian infiltration in mice.

physiology↗

bioRxiv2019

Aging induces Nlrp3 inflammasome dependent adipose B cell expansion to impair metabolic homeostasis

Visceral adiposity in elderly is associated with alterations in adipose tissue immune cells leading to inflammation and metabolic dysfunction. The Nlrp3 inflammasome is a critical regulator of macrophage activation, inflammation, and immunometabolism in visceral adipose tissue during aging; however, the potential contribution of adipose tissue B cells is unexplored. Here, we show that aging expands adipose-resident B cells and fat-associated lymphoid clusters (FALCs) in visceral white adipose tissue. Adipose tissue B cells exhibit a memory-like B cell profile similar to the phenotype of aged B cells that are increased in spleen of old mice. Mechanistically, the age-induced FALC formation and adipose B cell expansion, but not B cell transcriptional program, is dependent on the Nlrp3 inflammasome. Furthermore, B cell depletion in aged mice restores lipolysis and defense against loss of core body temperature during cold stress. These data reveal that inhibiting Nlrp3-dependent B cell accumulation can be targeted to reverse metabolic impairment in aging adipose tissue.\n\nHighlights- Adipose-resident aged B cells are increased in fat-associated lymphoid clusters (FALC)\n\n- FALC formation and adipose-resident B cell expansion during aging are regulated by the Nlrp3 inflammasome\n\n- Nlrp3 and B cell depletion in aging restores lipolysis and improves cold tolerancea

immunology↗