Biology subjects

Kronenfeld, J. M.

Publications and source records attributed to Kronenfeld, J. M..

4 recordsLinked to original sources

bioRxiv2022

Obesity-Associated Alterations In Lung Function In Mice Measured With Head-Out Plethysmography

Declines in lung function worsen quality of life and increase the risk of mortality. Obesity and non-alcoholic fatty liver disease are associated with worsened lung function. To investigate this association, we assessed lung function in lean and diet-induced obese conscious mice using our newly developed leak-free head-out plethysmography system. Obesity was associated with increased volume (P<0.0001), minute ventilation (volume per minute; P<0.0001), mid-expiratory flow (flow rate at 50% expiratory volume; P<0.0001), end-inspiratory pause (pause at end of inspiration; P<0.0001) and decreased expiratory time (P<0.0001). We next compared the response to methacholine (0, 25, 50, 100 mg/ml in PBS flow 0.2ml/30sec) measured using our head-out plethysmography system with forced oscillation technique (using the standard flexiVent system) measures taken in the same mice. Many of the measures gathered using head-out plethysmography were associated with measures collected using the forced oscillation technique. Minute ventilation was most significantly associated with maximal airway resistance, maximal airway elastance, tissue damping, and tissue elastance (r=-0.59 P<0.0001; r=-0.54 P<0.005; r=-0.48 P<0.005; r=-0.40 P<0.005 respectively). Volume, corrected for energy expenditure, was most significantly associated with maximal resistance of the conducting airways (r=-0.57 P<0.0001). Although fatty liver is associated with changes in lung function, we found neither hepatic vagotomy nor knocking down obesity-induced hepatic GABA production improved lung function in obese mice. Still, our head-out plethysmography system is ideal for assessing the response to interventions aimed at improving obesity-associated declines in lung function.

physiology↗

bioRxiv2021

A Leak-Free Head-Out Plethysmography System to Accurately Assess Lung Function in Mice

Mice are a valuable model for elegant studies of complex, systems-dependent diseases, including pulmonary diseases. Current tools to assess lung function in mice are either terminal or lack accuracy. We set out to develop a low-cost, accurate, head-out variable-pressure plethysmography system to allow for repeated, non-terminal measurements of lung function in mice. Current head-out plethysmography systems are limited by air leaks that prevent accurate measures of volume and flow. We designed an inflatable cuff that encompasses the mouses neck preventing air leak. We wrote corresponding software to collect and analyze the data, remove movement artifacts, and automatically calibrate each dataset. This software calculates inspiratory/expiratory volume, inspiratory/expiratory time, breaths per minute, enhanced pause, mid-expiratory flow, and end-inspiratory pause. To validate the use, we established our plethysmography system accurately measured tidal breathing, the bronchoconstrictive response to methacholine, sex and age associated changes in breathing, and breathing changes associated with house dust mite sensitization. Our estimates of volume, flow, and timing of breaths are in line with published estimates, we observed dose-dependent decreases in volume and flow in response to methacholine (P < 0.05), increased lung volume and decreased breathing rate with aging (P < 0.05), and that house dust mite sensitization decreased tidal volume and flow (P <0.05) while exacerbating the methacholine induced increases in inspiratory and expiratory time (P < 0.05). We describe an accurate, sensitive, low-cost, head-out plethysmography system that allows for longitudinal studies of pulmonary disease in mice. New & NoteworthyWe describe a variable-pressure head-out plethysmography system that can be used to assess lung function in mice. A balloon cuff that inflates around the mouses neck prevents air leak, allowing for accurate measurements of lung volume and air flow. Custom software facilitates system calibration, removes movement artifacts, and eases data analysis. The system was validated by measuring tidal breathing, responses to methacholine, and changes associated with house dust mite sensitization, sex, and aging. Contributions to StudyO_LIStephanie Bruggink: development of head-out plethysmography chamber, measurement of breathing, data analysis, prepared manuscript C_LIO_LIKyle Kentch: development of head-out plethysmography chamber, programmed software to collect and analyze data, prepared manuscript C_LIO_LIJason Kronenfeld: development of tools to analyze data, analysis of data C_LIO_LIBenjamin Renquist: development of head-out plethysmography chamber, statistical analysis, prepared manuscript C_LI

physiology↗

bioRxiv2020

Food intake dependent and independent effects of heat stress on lactation and mammary gland development

With a growing population, a reliable food supply is increasingly important. Heat stress reduces livestock meat and milk production. Genetic selection of high producing animals increases endogenous heat production, while climate change increases exogenous heat exposure. Both sources of heat exacerbate the risk of heat-induced depression of production. Rodents are valuable models to understand mechanisms conserved across species. Heat exposure suppresses feed intake across homeothermic species including rodents and production animal species. We assessed the response to early-mid lactation or late gestation heat exposure on milk production and mammary gland development/function, respectively. Using pair-fed controls we experimentally isolated the food intake dependent and independent effects of heat stress on mammary function and mass. Heat exposure (35{degrees}C, relative humidity 50%) decreased daily food intake. When heat exposure occurred during lactation, hypophagia accounted for approximately 50% of the heat stress induced hypogalactia. Heat exposure during middle to late gestation suppressed food intake, which was fully responsible for the lowered mammary gland weight of dams at parturition. However, the impaired mammary gland function in heat exposed dams measured by metabolic rate and lactogenesis could not be explained by depressed food consumption. In conclusion, mice recapitulate the depressed milk production and mammary gland development observed in dairy species while providing insight regarding the role of food intake. This opens the potential to apply genetic, experimental and pharmacological models unique to mice to identify the mechanism by which heat is limiting animal production. Summary StatementsThis study demonstrates that heat stress decreases lactation and mammary development through food intake dependent and independent mechanisms.

physiology↗

bioRxiv2020

A Critical Role of Hepatic GABA in The Metabolic Dysfunction and Hyperphagia of Obesity

Hepatic lipid accumulation is a hallmark of type II diabetes (T2D) and associated with hyperinsulinemia, insulin resistance, and hyperphagia. Hepatic synthesis of GABA, catalyzed by GABA-transaminase (GABA-T), is upregulated in obese mice. To assess the role of hepatic GABA production in obesity-induced metabolic and energy dysregulation, we treated mice with two pharmacologic GABA-T inhibitors and knocked down hepatic GABA-T expression using an antisense oligonucleotide. Hepatic GABA-T inhibition and knockdown decreased basal hyperinsulinemia and hyperglycemia, and improved glucose intolerance. GABA-T knockdown improved insulin sensitivity assessed by hyperinsulinemic-euglycemic clamps in obese mice. Hepatic GABA-T knockdown also decreased food intake and induced weight loss without altering energy expenditure in obese mice. Data from people with obesity support the notion that hepatic GABA production and transport are associated with serum insulin, HOMA-IR, T2D, and BMI. These results support a key role for hepatocyte GABA production in the dysfunctional glucoregulation and feeding behavior associated with obesity.

physiology↗