Celebrating a decade of exercise physiology and metabolism research in physiological reports.

During its first decade of life, Physiological Reports has become a home for well-conceived and rigorously performed exercise physiology and metabolism studies. The breadth of research within this area is impressive, covering exercise-induced increases in skeletal muscle gene expression to the effects of exercise on the gut microbiome. The purpose of the current review is to highlight some of the impactful exercise physiology and metabolism papers published in the journal and to look ahead to what areas exercise physiology publications might address in the next 10 years.

Amylin receptor agonism enhances the effects of liraglutide in protecting against the acute metabolic side effects of olanzapine.

Olanzapine is a second-generation antipsychotic (AP) used in the management of schizophrenia. Although effective at reducing psychoses, APs cause rapid hyperglycemia, insulin resistance, and dyslipidemia, an effect mediated in part by glucagon. We tested if amylin, a hormone that reduces glucagon, or the amylin receptor agonist pramlintide would protect against acute olanzapine-induced impairments in glucose and lipid homeostasis alone or in combination with other glucose-lowering agents such as liraglutide. We demonstrated that pramlintide lowered olanzapine-induced increases in glucagon:insulin ratio with a trend to protect against excursions in blood glucose. There was an additive effect of pramlintide and liraglutide in protecting against olanzapine-induced hyperglycemia, which was mirrored by reductions in glucagon and attenuated markers of dyslipidemia. Our findings provide evidence that pramlintide, although moderately protective against some aspects of olanzapine-induced metabolic dysfunction, can be used to enhance the protective effects of other interventions against acute olanzapine-induced metabolic dysfunction.

Salsalate and/or metformin therapy confer beneficial metabolic effects in olanzapine treated female mice.

Antipsychotic medications are used in the management of schizophrenia and a growing number of off-label conditions. While effective at reducing psychoses, these drugs possess noted metabolic side effects including weight gain, liver lipid accumulation and disturbances in glucose and lipid metabolism. To counter the side effects of antipsychotics standard of care has typically included metformin. Unfortunately, metformin does not protect against antipsychotic induced metabolic disturbances in all patients and thus additional treatment approaches are needed. One potential candidate could be salsalate, the prodrug of salicylate, which acts synergistically with metformin to improve indices of glucose and lipid metabolism in obese mice. The purpose of the current investigation was to compare the effects of salsalate, metformin and a combination of both drugs, on weight gain and indices of metabolic health in female mice treated with the antipsychotic, olanzapine. Herein we demonstrate that salsalate was equally as effective as metformin in protecting against olanzapine induced weight gain and liver lipid accumulation with no additional benefit of combining both drugs. Conversely, metformin treatment, either alone or in combination with salsalate, improved indices of glucose metabolism and increased energy expenditure in olanzapine treated mice. Collectively, our findings provide evidence that dual therapy with both metformin and salsalate could be an efficacious approach with which to dampen the metabolic consequences of antipsychotic medications.

Liver triacylglycerol accumulation but not postprandial lipemia is reduced by a skim milk powder diet in male rats.

Increases in postprandial lipids are linked to the development of cardiometabolic and fatty liver disease. Prior work has suggested that dairy possesses beneficial cardiometabolic effects and thus the aim of the current investigation was to test the hypotheses that the habitual consumption of dairy, in the form of skim milk powder (SMP), would protect against increases in circulating lipids and liver lipid accumulation following an oral fat challenge in rats. Male rats were fed either a semipurified low-fat control diet with casein or a diet with an equivalent amount of protein (∼13% kcal) provided through skim milk powder (SMP) for 6 weeks (n = 40/group). Rats were then given an oral gavage of palm oil (5 mL/kg body weight) or an equivalent volume of water, and serum and liver were harvested 90 minutes or 4 hours after. Rats fed the SMP diet gained less weight than controls but there were no differences in glucose tolerance between groups. The fat gavage increased serum lipids in both diet groups, whereas there was a main effect of the fat challenge to increase, and the SMP diet, to decrease liver triacylglycerol accumulation. The percentage of saturated and monounsaturated fatty acids and the protein content/activity of lipogenic enzymes were reduced in livers from SMP-fed rats, whereas the percentage of polyunsaturated fatty acids was increased. In summary, we provide evidence that SMP consumption, although not protecting against postprandial lipemia, markedly attenuates triacylglycerol accumulation and the relative amount of saturated and monounsaturated fatty acids in the liver.

A moderate-fat diet containing soy protein does not differentially impact energy balance in male and female mice compared to dairy protein.

Dairy and nondairy plant-based alternative proteins are reported to differentially influence body weight; however, most research has compared plant-based alternatives with isolated dairy proteins rather than a complete milk protein (containing casein and whey). This is notable given that people do not generally consume isolated dairy proteins. Therefore, the present study aimed to investigate the impact of a soy protein isolate (SPI) on factors influencing body weight gain in male and female mice in comparison to skim milk powder (SMP). Based on current knowledge in rodents, we hypothesized that SPI would promote body weight gain compared with SMP. Mice (n = 8 per sex per diet) consumed a moderate-fat diet (35% kcal from fat) containing either SPI or SMP for 8 weeks. Body weight and food intake were measured weekly. Energy expenditure, physical activity, and substrate use were measured using metabolic cages. Fecal energy content was measured with bomb calorimetry. Body weight gain and food intake during the 8-week feeding study was not different in mice consuming either SPI or SMP; however, males had a higher body weight, adiposity, and feed efficiency compared with females (all P < .05). Fecal energy content was approximately 7% higher in both male and female mice fed the SPI diet compared with the SMP diet. Neither protein source affected substrate utilization, physical activity, or energy expenditure. Physical activity in the dark phase trended higher in females compared with males (P = .0732). The present study suggests that the consumption of SPI in the context of a moderate-fat diet has little impact on numerous factors influencing body weight regulation in male and female mice compared with a complete milk protein.

Enhancing endogenous levels of GLP1 dampens acute olanzapine induced perturbations in lipid and glucose metabolism.

Olanzapine is a second-generation antipsychotic (SGA) used in the treatment of schizophrenia and several on- and off-label conditions. While effective in reducing psychoses, acute olanzapine treatment causes rapid hyperglycemia, insulin resistance, and dyslipidemia and these perturbations are linked to an increased risk of developing cardiometabolic disease. Pharmacological agonists of the glucagon-like peptide-1 (GLP1) receptor have been shown to offset weight-gain associated with chronic SGA administration and mitigate the acute metabolic side effects of SGAs. The purpose of this study was to determine if increasing endogenous GLP1 is sufficient to protect against acute olanzapine-induced impairments in glucose and lipid homeostasis. Male C57BL/6J mice were treated with olanzapine, in the absence or presence of an oral glucose tolerance test (OGTT), and a combination of compounds to increase endogenous GLP1. These include the non-nutritive sweetener allulose which acts to induce GLP1 secretion but not other incretins, the DPPiv inhibitor sitagliptin which prevents degradation of active GLP1, and an SSTR5 antagonist which relieves inhibition on GLP1 secretion. We hypothesized that this cocktail of agents would increase circulating GLP1 to supraphysiological concentrations and would protect against olanzapine-induced perturbations in glucose and lipid homeostasis. We found that 'triple treatment' increased both active and total GLP1 and protected against olanzapine-induced perturbations in lipid and glucose metabolism under glucose stimulated conditions and this was paralleled by an attenuation in the olanzapine induced increase in the glucagon:insulin ratio. Our findings provide evidence that pharmacological approaches to increase endogenous GLP1 could be a useful adjunct approach to reduce acute olanzapine-induced perturbations in lipid and glucose metabolism.

Acute interleukin-6 modulates key enzymes involved in prefrontal cortex and hippocampal amyloid precursor protein processing.

Exercise has been shown to be beneficial for individuals with Alzheimer's disease (AD). In rodent models of AD, exercise decreases the amyloidogenic processing of the amyloid precursor protein (APP). Although it remains unclear as to how exercise is promoting this shift away from pathological APP processing, there is emerging evidence that exercise-induced factors released from peripheral tissues may facilitate these alterations in brain APP processing. Interleukin-6 (IL-6) is released from multiple organs into peripheral circulation during exercise and is among the most characterized exerkines. The purpose of this study is to examine whether acute IL-6 can modulate key enzymes responsible for APP processing, namely, a disintegrin and metalloproteinase 10 (ADAM10) and ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1), which initiate the nonamyloidogenic and amyloidogenic cascades, respectively. Male 10-wk-old C57BL/6J mice underwent acute treadmill exercise bout or were injected with either IL-6 or a PBS control 15 min prior to tissue collection. ADAM10 and BACE1 enzyme activity, mRNA, and protein expression, as well as downstream markers of both cascades, including soluble APPα (sAPPα) and soluble APPß (sAPPß), were examined. Exercise increased circulating IL-6 and brain IL-6 signaling (pSTAT3 and Socs3 mRNA). This occurred alongside a reduction in BACE1 activity and an increase in ADAM10 activity. IL-6 injection reduced BACE1 activity and increased sAPPα protein content in the prefrontal cortex. In the hippocampus, IL-6 injection decreased BACE1 activity and sAPPß protein content. Our results show that acute IL-6 injection increases markers of the nonamyloidogenic cascade and decreases markers of the amyloidogenic cascade in the cortex and hippocampus of the brain.NEW & NOTEWORTHY It is becoming evident that exercise modulates APP processing and can reduce amyloid-beta (Aß) peptide production. Our data help to explain this phenomenon by highlighting IL-6 as an exercise-induced factor that lowers pathological APP processing. These results also highlight brain regional differences in response to acute IL-6.

Thermoneutral housing and preexisting obesity do not abolish the sexually dimorphic effects of olanzapine on weight gain in mice.

OBJECTIVE: In contrast to what is seen clinically, male mice are resistant to antipsychotic-induced obesity. This is problematic as preclinical studies examining mechanisms of antipsychotic-induced metabolic dysfunction might be relevant to only half the population. This study sought to determine whether housing mice at thermoneutrality and under conditions of preexisting obesity, steps that have not been previously considered, would uncover a greater obesogenic effect of the antipsychotic olanzapine (OLZ). METHODS: C57BL6/J mice were fed a low- or high-fat diet (HFD) for 4 weeks and then switched to a control HFD or an HFD supplemented with OLZ for 6 weeks. RESULTS: Irrespective of obesity, OLZ treatment attenuated weight gain and increased energy expenditure in male mice. In females, OLZ increased food intake and potentiated weight gain in mice with preexisting obesity. CONCLUSIONS: Despite taking steps to increase clinical translatability, this study did not unmask an obesogenic effect of OLZ in male mice. Interestingly, prior studies in female mice could have been underestimating the metabolic consequences of OLZ by not considering the importance of preexisting obesity. Uncovering the mechanisms conferring resistance to weight gain in males may provide clues for approaches to counter the metabolic side effects of antipsychotics clinically.

Antipsychotic-Induced Alterations in Lipid Turnover.

Schizophrenia is a debilitating psychiatric disorder that is treated with antipsychotics. However, despite their efficacy, antipsychotics increase the risk of metabolic disorders in a population that suffers from premature cardiovascular death. Published reports to date strongly suggest that antipsychotic-induced alterations in lipid metabolism are part of the causal relationship between antipsychotic treatment and both metabolic and cardiovascular disease. Notably, some of the adverse effects of antipsychotics on lipid metabolism are independent of antipsychotic-induced weight gain. Moreover, some antipsychotics also have beneficial effects on certain aspects of lipid metabolism. In this review, we summarize the current knowledge regarding how antipsychotics modulate lipid turnover at the whole-body, tissue, and cellular levels. We also highlight gaps in the literature, especially with respect to the intracellular mechanisms through which antipsychotics affect lipid metabolism.

GDF15 is an exercise-induced hepatokine regulated by glucagon and insulin in humans.

Objective: Growth differentiation factor (GDF)-15 is implicated in regulation of metabolism and circulating GDF15 increases in response to exercise. The source and regulation of the exercise-induced increase in GDF15 is, however not known. Method: Plasma GDF15 was measured by ELISA under the following conditions: 1) Arterial-to-hepatic venous differences sampled before, during, and after exercise in healthy male subjects (n=10); 2) exogenous glucagon infusion compared to saline infusion in resting healthy subjects (n=10); 3) an acute exercise bout with and without a pancreatic clamp (n=6); 4) healthy subjects for 36 hours (n=17), and 5) patients with anorexia nervosa (n=25) were compared to healthy age-matched subjects (n=25). Tissue GDF15 mRNA content was determined in mice in response to exhaustive exercise (n=16). Results: The splanchnic bed released GDF15 to the circulation during exercise and increasing the glucagon-to-insulin ratio in resting humans led to a 2.7-fold (P<0.05) increase in circulating GDF15. Conversely, inhibiting the exercise-induced increase in the glucagon-to-insulin ratio blunted the exercise-induced increase in circulating GDF15. Fasting for 36 hours did not affect circulating GDF15, whereas resting patients with anorexia nervosa displayed elevated plasma concentrations (1.4-fold, P<0.05) compared to controls. In mice, exercise increased GDF15 mRNA contents in liver, muscle, and adipose tissue. Conclusion: In humans, GDF15 is a "hepatokine" which increases during exercise and is at least in part regulated by the glucagon-to-insulin ratio. Moreover, chronic energy deprivation is associated with elevated plasma GDF15, which supports that GDF15 is implicated in metabolic signalling in humans.

Ketogenic diet-induced weight loss occurs independent of housing temperature and is followed by hyperphagia and weight regain after cessation in mice.

Ketogenic diets (KDs) are a popular tool used for weight management. Studies in mice have demonstrated that KDs reduce food intake, increase energy expenditure and cause weight loss. These studies were completed at room temperature, a condition below the animal's thermal neutral zone which induces thermal stress. As energy intake and expenditure are sensitive to environmental temperature it is not clear if a KD would exert the same beneficial effects under thermal neutral conditions. Adherence to restrictive diets is poor and consequently it is important to examine the effects, and underlying mechanisms, of cycling from a ketogenic to an obesogenic diet. The purpose of the current study was to determine if housing temperature impacted the effects of a KD in obese mice and to determine if the mechanisms driving KD-induced weight loss reverse when mice are switched to an obesogenic high fat diet. We demonstrate that KD-induced reductions in food intake, increases in energy expenditure, weight loss and improvements in glucose homeostasis are not dependent upon housing temperature. KD-induced weight loss seems to be largely explained by reductions in caloric intake while cycling mice back to an obesogenic diet following a period of KD feeding leads to hyperphagia-induced weight gain. Collectively, our results suggest that prior findings with mice fed a KD at room temperature are likely not an artifact of how mice were housed and that initial changes in weight when transitioning from an obesogenic to a ketogenic diet or back are largely dependent on food intake. KEY POINTS: Ketogenic diets reduce food intake, increase energy expenditure and cause weight loss in rodents Prior preclinical studies have been completed at room temperature, a condition which induces thermal stress and limits clinical translatability Here it is demonstrated that ketogenic diet-induced reductions in food intake, increases in energy expenditure, weight loss and improvements in glucose homeostasis are similar in mice housed at room temperature or thermal neutrality Ketogenic diet-induced reductions in food intake appear to explain a large degree of weight loss. Similarly, switching mice from a ketogenic to an obesogenic diet leads to hyperphagia-mediated weight gain.

Influence of weighted downhill running training on serial sarcomere number and work loop performance in the rat soleus.

Increased serial sarcomere number (SSN) has been observed in rats following downhill running training due to the emphasis on active lengthening contractions; however, little is known about the influence on dynamic contractile function. Therefore, we employed 4 weeks of weighted downhill running training in rats, then assessed soleus SSN and work loop performance. We hypothesised trained rats would produce greater net work output during work loops due to a greater SSN. Thirty-one Sprague-Dawley rats were assigned to a training or sedentary control group. Weight was added during downhill running via a custom-made vest, progressing from 5-15% body mass. Following sacrifice, the soleus was dissected, and a force-length relationship was constructed. Work loops (cyclic muscle length changes) were then performed about optimal muscle length (LO) at 1.5-3-Hz cycle frequencies and 1-7-mm length changes. Muscles were then fixed in formalin at LO. Fascicle lengths and sarcomere lengths were measured to calculate SSN. Intramuscular collagen content and crosslinking were quantified via a hydroxyproline content and pepsin-solubility assay. Trained rats had longer fascicle lengths (+13%), greater SSN (+8%), and a less steep passive force-length curve than controls (P<0.05). There were no differences in collagen parameters (P>0.05). Net work output was greater (+78-209%) in trained than control rats for the 1.5-Hz work loops at 1 and 3-mm length changes (P<0.05), however, net work output was more related to maximum specific force (R2=0.17-0.48, P<0.05) than SSN (R2=0.03-0.07, P=0.17-0.86). Therefore, contrary to our hypothesis, training-induced sarcomerogenesis likely contributed little to the improvements in work loop performance. This article has an associated First Person interview with the first author of the paper.

Gut microbiome in schizophrenia and antipsychotic-induced metabolic alterations: a scoping review.

Schizophrenia (SCZ) is a severe mental disorder with high morbidity and lifetime disability rates. Patients with SCZ have a higher risk of developing metabolic comorbidities such as obesity and diabetes mellitus, leading to increased mortality. Antipsychotics (APs), which are the mainstay in the treatment of SCZ, increase the risk of these metabolic perturbations. Despite extensive research, the mechanism underlying SCZ pathophysiology and associated metabolic comorbidities remains unclear. In recent years, gut microbiota (GMB) has been regarded as a 'chamber of secrets', particularly in the context of severe mental illnesses such as SCZ, depression, and bipolar disorder. In this scoping review, we aimed to investigate the underlying role of GMB in the pathophysiology of SCZ and metabolic alterations associated with APs. Furthermore, we also explored the therapeutic benefits of prebiotic and probiotic formulations in managing SCZ and AP-induced metabolic alterations. A systematic literature search yielded 46 studies from both preclinical and clinical settings that met inclusion criteria for qualitative synthesis. Preliminary evidence from preclinical and clinical studies indicates that GMB composition changes are associated with SCZ pathogenesis and AP-induced metabolic perturbations. Fecal microbiota transplantation from SCZ patients to mice has been shown to induce SCZ-like behavioral phenotypes, further supporting the plausible role of GMB in SCZ pathogenesis. This scoping review recapitulates the preclinical and clinical evidence suggesting the role of GMB in SCZ symptomatology and metabolic adverse effects associated with APs. Moreover, this scoping review also discusses the therapeutic potentials of prebiotic/probiotic formulations in improving SCZ symptoms and attenuating metabolic alterations related to APs.

Fasting or the short-term consumption of a ketogenic diet protects against antipsychotic-induced hyperglycaemia in mice.

Antipsychotic (AP) medications, such as olanzapine (OLZ), are used in the treatment of schizophrenia and a growing number of 'off-label' conditions. A single dose of OLZ causes robust increases in blood glucose within minutes of treatment. The purpose of the current study was to investigate whether interventions that increase circulating ketone bodies (fasting, ß-hydroxybutyrate (ßHB), ketone esters or a ketogenic diet (KD)) would be sufficient to protect against the acute metabolic side effects of OLZ. We demonstrate that fasting or the short-term consumption of a KD protects against OLZ-induced hyperglycaemia, independent of alterations in whole-body insulin action, and in parallel with a blunted rise in serum glucagon. Interestingly, the effects of fasting and KDs were not recapitulated by acutely increasing circulating concentrations of ketone bodies through treatment with ßHB or oral ketone esters, approaches which increase ketone bodies to physiological or supra-physiological levels, respectively. Collectively, our findings demonstrate that fasting and the short-term consumption of a KD can protect against acute AP-induced perturbations in glucose homeostasis, whereas manipulations which acutely increase circulating ketone bodies do not elicit the same beneficial effects. KEY POINTS: Antipsychotic medications cause rapid and robust increases in blood glucose. Co-treatment approaches to offset these harmful metabolic side effects have not been identified. We demonstrate that fasting or the consumption of a short-term ketogenic diet, but not treatment with ß-hydroxybutyrate or oral ketone esters, protects against acute antipsychotic-induced hyperglycaemia. The protective effects of fasting and ketogenic diets were paralleled by reductions in serum glucagon, but not improvements in whole-body insulin action.

The glucose lowering effects of CL 316,243 dissipate with repeated use and are rescued bycilostamide.

Repeated activation of the beta 3 adrenergic receptor (ß3AR) with the agonist CL 316,243 (CL) results in remodeling of white adipose tissue (WAT) characterized by increased mitochondrial enzymes and expression of uncoupling protein 1 (UCP1). ß3AR activation also has profound acute metabolic effects including rapidly decreasing blood glucose, secondary to fatty acid-induced increases in insulin, and increasing energy expenditure. The acute (single dose) effects of ß3AR activation have largely been examined in treatment naive animals and under room temperature housing conditions. The current study examined if repeated CL treatment would lead to an attenuation of acute metabolic effects of CL treatment under thermoneutral housing conditions and if this could be rescued with cilostamide, a phosphodiesterase inhibitor. We provide evidence demonstrating that the acute effects of CL to increase serum fatty acids and insulin and reduce blood glucose, but not increases in energy expenditure, are attenuated in mice following repeated treatment with CL. This occurs in parallel with reductions in indices of protein kinase A signaling in WAT including the phosphorylation of hormone sensitive lipase. The findings of attenuated serum fatty acid, insulin, and blood glucose responses were confirmed in both high-fat fed and UCP1-/- mice repeatedly treated with CL. Desensitization to CL in mice was rescued by cilostamide. Herein, we provide evidence that the glucose lowering, but not thermogenesis inducing, effects of CL are attenuated with repeated treatment and can be rescued by cilostamide. The findings of this study point toward novel adjunct treatment approaches that could be used to maximize therapeutic, glucose lowering effects of ß3AR agonists.

Topical application of the pharmacological cold mimetic menthol stimulates brown adipose tissue thermogenesis through a TRPM8, UCP1, and norepinephrine dependent mechanism in mice housed at thermoneutrality.

Increasing whole-body energy expenditure via the pharmacological activation of uncoupling protein 1 (UCP1)-dependent brown adipose tissue (BAT) thermogenesis is a promising weight management strategy, yet most therapeutics studied in rodents to date either induce compensatory increases in energy intake, have thermogenic effects that are confounded by sub-thermoneutral housing temperatures or are not well tolerated in humans. Here, we sought to determine whether the non-invasive topical application of the pharmacological cold mimetic and transient receptor potential (TRP) cation channel subfamily M member 8 (TRPM8) agonist L-menthol (MNTH), could be used to stimulate BAT thermogenesis and attenuate weight gain in mice housed at thermoneutrality. Using three different strains of mice and multiple complimentary approaches to quantify thermogenesis in vivo, coupled with ex vivo models to quantify direct thermogenic effects, we were able to convincingly demonstrate the following: (1) acute topical MNTH application induces BAT thermogenesis in a TRPM8- and UCP1-dependent manner; (2) MNTH-induced BAT thermogenesis is sufficient to attenuate weight gain over time without affecting energy intake in lean and obese mice; (3) the ability of topical MNTH application to stimulate BAT thermogenesis is mediated, in part, by a central mechanism involving the release of norepinephrine. These data collectively suggest that topical application of MNTH may be a promising weight management strategy.

Ckmt1 is Dispensable for Mitochondrial Bioenergetics Within White/Beige Adipose Tissue.

Within brown adipose tissue (BAT), the brain isoform of creatine kinase (CKB) has been proposed to regulate the regeneration of ADP and phosphocreatine in a futile creatine cycle (FCC) that stimulates energy expenditure. However, the presence of FCC, and the specific creatine kinase isoforms regulating this theoretical model within white adipose tissue (WAT), remains to be fully elucidated. In the present study, creatine did not stimulate respiration in cultured adipocytes, isolated mitochondria or mouse permeabilized WAT. Additionally, while creatine kinase ubiquitous-type, mitochondrial (CKMT1) mRNA and protein were detected in human WAT, shRNA-mediated reductions in Ckmt1 did not decrease submaximal respiration in cultured adipocytes, and ablation of CKMT1 in mice did not alter energy expenditure, mitochondrial responses to pharmacological ß3-adrenergic activation (CL 316, 243) or exacerbate the detrimental metabolic effects of consuming a high-fat diet. Taken together, these findings solidify CKMT1 as dispensable in the regulation of energy expenditure, and unlike in BAT, they do not support the presence of FCC within WAT.