Circannual Patterns of Adipose Tissue Characteristics in a Hibernator, the Thirteen-lined Ground Squirrel (Ictidomys tridecemlineatus)

Obligate hibernators express circannual patterns of body mass and hibernation, which persist under constant laboratory conditions. I hypothesized that in the 13-lined ground squirrel (Ictidomys tridecemlineatus) thermogenic brown adipose tissue (BAT) and lipid storing white adipose tissue (WAT) volume would follow a circannual pattern. I housed animals at either 25°C (thermoneutral) or 5°C with 12h L:12h D photoperiods for an entire year. I determined volume and water-fat ratio of WAT and BAT using magnetic resonance imaging (MRI). BAT volume follows a circannual pattern in both conditions, increasing prior to winter, decreasing in late winter with no change in water-fat ratio. Both body mass and WAT volume of cold-housed animals declined throughout the winter and recovered after hibernation. By contrast, thermoneutral housing produced no circannual pattern in body mass even though WAT volume declined in late winter. Warm-housed animals never entered torpor indicating that they might not be obligate hibernators

Sexism of Fat: Is it sufficient to use only one sex in obesity research?

There is a weight issue weighing down the public health care systems across the world. Although obesity is prevalent in both males and females, the location of fat and impact on cardiometabolic health is strikingly different. These differences are apparent in the clinical setting, but there remains a bias towards using a single sex in mouse models to create simpler and cheaper experiments. The bias towards using a single sex in experiments skews the results and only offers translational research to one half of the human population. We examined sex differences and their effect on obesity by inducing obesity in both male and female mice by feeding them high fat diet (HFD) for 10 weeks. Mice were weighed weekly and after 10 weeks of HFD feeding, mice underwent metabolic tests to determine the impact of obesity. Male mice became obese after only 1 week of HFD feeding, however it took female mice 9 weeks of HFD feeding to become obese. Male mice were more susceptible to diabetes and male mice lost increased metabolic difference when fed HFD. This study highlights the importance of using both sexes to study obesity and associated diseases while highlighting novel differences in metabolism between sexes

Identification of a lipid-rich depot in the orbital cavity of the thirteen-lined ground squirrel

We discovered a previously undescribed orbital lipid depot in the thirteen-lined ground squirrel during the first ever magnetic resonance image (MRI) of this common experimental model of mammalian hibernation. In animals housed at constant ambient temperatures (5°C or 25°C, 12 h:12 h light:dark photoperiod), the volume of this depot increased in the autumn and decreased in the spring, suggesting an endogenous circannual pattern. Water-fat MRI revealed that throughout the year this depot is composed of ∼40% lipid, similar to brown adipose tissue (BAT). During arousal from torpor, thermal images showed higher surface temperatures near this depot before the rest of the head warmed, suggesting a thermoregulatory function. This depot, however, does not contain uncoupling protein 1, a BAT biomarker, or uncoupling protein 3. Histology shows blood vessels in close proximity to each other, suggesting it may serve as a vascular rete, perhaps to preferentially warm the eye and brain during arousals

Identification of a lipid-rich depot in the orbital cavity of the 13-lined ground squirrel

We discovered a previously undescribed orbital lipid depot in the 13-lined ground squirrel during the first ever magnetic resonance image (MRI) of this common experimental model of mammalian hibernation. In animals housed at constant ambient temperatures (5ºC or 25ºC, 12h L:12h D photoperiod) the volume of this depot increased in the autumn and decreased in the spring, suggesting an endogenous circannual pattern. Water-fat MRI revealed that throughout the year this depot is composed of ~40% lipid, similar to brown adipose tissue (BAT). During arousal from torpor, thermal images showed higher surface temperatures near this depot before the rest of the head warmed, suggesting a thermoregulatory function. This depot, however, does not contain uncoupling protein 1, a BAT biomarker, or uncoupling protein 3. Histology shows blood vessels in close proximity to each other, suggesting it may serve as a vascular rete, perhaps to preferentially warm the eye and brain during arousals

Association between type 2 diabetes and changes in myocardial structure, contractile function, energetics, and blood flow before and after aortic valve replacement in patients with severe aortic stenosis

BACKGROUND: Type 2 diabetes (T2D) is associated with an increased risk of left ventricular dysfunction after aortic valve replacement (AVR) in patients with severe aortic stenosis (AS). Persistent impairments in myocardial energetics and myocardial blood flow (MBF) may underpin this observation. Using phosphorus magnetic resonance spectroscopy and cardiovascular magnetic resonance, this study tested the hypothesis that patients with severe AS and T2D (AS-T2D) would have impaired myocardial energetics as reflected by the phosphocreatine to ATP ratio (PCr/ATP) and vasodilator stress MBF compared with patients with AS without T2D (AS-noT2D), and that these differences would persist after AVR. METHODS: Ninety-five patients with severe AS without coronary artery disease awaiting AVR (30 AS-T2D and 65 AS-noT2D) were recruited (mean, 71 years of age [95% CI, 69, 73]; 34 [37%] women). Thirty demographically matched healthy volunteers (HVs) and 30 patients with T2D without AS (T2D controls) were controls. One month before and 6 months after AVR, cardiac PCr/ATP, adenosine stress MBF, global longitudinal strain, NT-proBNP (N-terminal pro-B-type natriuretic peptide), and 6-minute walk distance were assessed in patients with AS. T2D controls underwent identical assessments at baseline and 6-month follow-up. HVs were assessed once and did not undergo 6-minute walk testing. RESULTS: Compared with HVs, patients with AS (AS-T2D and AS-noT2D combined) showed impairment in PCr/ATP (mean [95% CI]; HVs, 2.15 [1.89, 2.34]; AS, 1.66 [1.56, 1.75]; P<0.0001) and vasodilator stress MBF (HVs, 2.11 mL min g [1.89, 2.34]; AS, 1.54 mL min g [1.41, 1.66]; P<0.0001) before AVR. Before AVR, within the AS group, patients with AS-T2D had worse PCr/ATP (AS-noT2D, 1.74 [1.62, 1.86]; AS-T2D, 1.44 [1.32, 1.56]; P=0.002) and vasodilator stress MBF (AS-noT2D, 1.67 mL min g [1.5, 1.84]; AS-T2D, 1.25 mL min g [1.22, 1.38]; P=0.001) compared with patients with AS-noT2D. Before AVR, patients with AS-T2D also had worse PCr/ATP (AS-T2D, 1.44 [1.30, 1.60]; T2D controls, 1.66 [1.56, 1.75]; P=0.04) and vasodilator stress MBF (AS-T2D, 1.25 mL min g [1.10, 1.41]; T2D controls, 1.54 mL min g [1.41, 1.66]; P=0.001) compared with T2D controls at baseline. After AVR, PCr/ATP normalized in patients with AS-noT2D, whereas patients with AS-T2D showed no improvements (AS-noT2D, 2.11 [1.79, 2.43]; AS-T2D, 1.30 [1.07, 1.53]; P=0.0006). Vasodilator stress MBF improved in both AS groups after AVR, but this remained lower in patients with AS-T2D (AS-noT2D, 1.80 mL min g [1.59, 2.0]; AS-T2D, 1.48 mL min g [1.29, 1.66]; P=0.03). There were no longer differences in PCr/ATP (AS-T2D, 1.44 [1.30, 1.60]; T2D controls, 1.51 [1.34, 1.53]; P=0.12) or vasodilator stress MBF (AS-T2D, 1.48 mL min g [1.29, 1.66]; T2D controls, 1.60 mL min g [1.34, 1.86]; P=0.82) between patients with AS-T2D after AVR and T2D controls at follow-up. Whereas global longitudinal strain, 6-minute walk distance, and NT-proBNP all improved after AVR in patients with AS-noT2D, no improvement in these assessments was observed in patients with AS-T2D. CONCLUSIONS: Among patients with severe AS, those with T2D demonstrate persistent abnormalities in myocardial PCr/ATP, vasodilator stress MBF, and cardiac contractile function after AVR; AVR effectively normalizes myocardial PCr/ATP, vasodilator stress MBF, and cardiac contractile function in patients without T2D

Environmental temperature effects on adipose tissue growth in a hibernator

Obligate hibernators express circannual patterns of body mass and hibernation, which persist under constant laboratory conditions. Brown adipose tissue (BAT) is important for thermogenesis during arousals from hibernation, whereas white adipose tissue (WAT) serves as energy storage and thermal insulation. The goal of this study was to investigate the effects of environmental temperature on BAT and WAT. We hypothesized that changes to environmental temperature would not influence the pattern of mass gain or BAT and WAT volume in the thirteen-lined ground squirrel (Ictidomys tridecemlineatus). To test this, we housed animals at thermoneutral 25°C (warm-housed) or 5°C (cold-housed), with the same photoperiod (12 h light:12 h dark) over an entire year. Throughout the year we measured the volume and water:fat ratio of WAT and BAT using magnetic resonance imaging (MRI). We found no evidence of torpor in the warm-housed animals, indicating that this species might not be an obligate hibernator, as previously assumed. Regardless of ambient temperature, BAT volume increased prior to winter, then decreased in late winter with no change in water:fat ratio. By contrast, both body mass and WAT volume of cold-housed animals declined throughout the winter and recovered after hibernation, but thermoneutral housing produced no circannual pattern in body mass, even though WAT volume declined in late winter. Cold exposure appears to be a primary regulator for WAT but BAT may exhibit an endogenous circannual rhythm in terms of depot volume

Long-chain ceramides are cell non-autonomous signals linking lipotoxicity to endoplasmic reticulum stress in skeletal muscle.

The endoplasmic reticulum (ER) regulates cellular protein and lipid biosynthesis. ER dysfunction leads to protein misfolding and the unfolded protein response (UPR), which limits protein synthesis to prevent cytotoxicity. Chronic ER stress in skeletal muscle is a unifying mechanism linking lipotoxicity to metabolic disease. Unidentified signals from cells undergoing ER stress propagate paracrine and systemic UPR activation. Here, we induce ER stress and lipotoxicity in myotubes. We observe ER stress-inducing lipid cell non-autonomous signal(s). Lipidomics identifies that palmitate-induced cell stress induces long-chain ceramide 40:1 and 42:1 secretion. Ceramide synthesis through the ceramide synthase 2 de novo pathway is regulated by UPR kinase Perk. Inactivation of CerS2 in mice reduces systemic and muscle ceramide signals and muscle UPR activation. The ceramides are packaged into extracellular vesicles, secreted and induce UPR activation in naïve myotubes through dihydroceramide accumulation. This study furthers our understanding of ER stress by identifying UPR-inducing cell non-autonomous signals