Impact of GLP-1 receptor agonist versus omega-3 fatty acids supplement on obesity-induced alterations of mitochondrial respiration.

Objective: To compare administration of the glucagon-like peptide-1 (GLP-1) analogue, exenatide, versus dietary supplementation with the omega-3 fatty acid-rich Calanus oil on obesity-induced alterations in mitochondrial respiration. Methods: Six-week-old female C57BL/6JOlaHSD mice were given high fat diet (HFD, 45% energy from fat) for 12 weeks to induce obesity. Thereafter, they were divided in three groups where one received exenatide (10 µg/kg/day) via subcutaneously implanted mini-osmotic pumps, a second group received 2% Calanus oil as dietary supplement, while the third group received HFD without any treatment. Animals were sacrificed after 8 weeks of treatment and tissues (skeletal muscle, liver, and white adipose tissue) were collected for measurement of mitochondrial respiratory activity by high-resolution respirometry, using an Oroboros Oxygraph-2k (Oroboros instruments, Innsbruck, Austria). Results: It was found that high-fat feeding led to a marked reduction of mitochondrial respiration in adipose tissue during all three states investigated - LEAK, OXPHOS and ETS. This response was to some extent attenuated by exenatide treatment, but not with Calanus oil treatment. High-fat feeding had no major effect on hepatic mitochondrial respiration, but exenatide treatment resulted in a significant increase in the various respiratory states in liver. Mitochondrial respiration in skeletal muscle was not significantly influenced by high-fat diet or any of the treatments. The precise evaluation of mitochondrial respiration considering absolute oxygen flux and ratios to assess flux control efficiency avoided misinterpretation of the results. Conclusions: Exenatide increased hepatic mitochondrial respiration in high-fat fed mice, but no clear beneficial effect was observed in skeletal muscle or fat tissue. Calanus oil did not negatively affect respiratory activity in these tissues, which maintains its potential as a dietary supplement, due to its previously reported benefits on cardiac function.

Impact of Obesity-Related Inflammation on Cardiac Metabolism and Function.

This review focuses on the role of adipose tissue in obese individuals in the development of metabolic diseases, and their consequences for metabolic and functional derangements in the heart. The general idea is that the expansion of adipocytes during the development of obesity gives rise to unhealthy adipose tissue, characterized by low-grade inflammation and the release of proinflammatory adipokines and fatty acids (FAs). This condition, in turn, causes systemic inflammation and elevated FA concentrations in the circulation, which links obesity to several pathologies, including impaired insulin signaling in cardiac muscle and a subsequent shift in myocardial substrate oxidation in favor of FAs and reduced cardiac efficiency. This review also argues that efforts to prevent obesity-related cardiometabolic disease should focus on anti-obesogenic strategies to restore normal adipose tissue metabolism.

Satisfaction and Functional Outcomes in Unicompartmental Compared with Total Knee Arthroplasty: Radiographically Matched Cohort Analysis.

Unicompartmental and total knee arthroplasty (UKA and TKA) have demonstrated excellent mid- and long-term outcomes and have been compared in clinical series for decades; however, to our knowledge, no study has sufficiently matched UKA and TKA cohorts on preoperative osteoarthritis severity. The purpose of this study was to evaluate patient-reported outcomes of radiographically and demographically matched UKA and TKA cohorts. METHODS: One hundred and thirty-five UKAs and 135 TKAs were matched by patient age, sex, body mass index, and American Society of Anesthesiologists Physical Status (ASA-PS) classification as well as preoperative osteoarthritis severity in medial and lateral tibiofemoral and patellofemoral compartments (Kellgren-Lawrence grading system). Patient-reported outcome measures for pain, function, activity level, and satisfaction were evaluated at minimum 1-year follow-up via components of the modern Knee Society Score, the University of California Los Angeles (UCLA) activity-level score, and a Likert satisfaction scale. RESULTS: The patients in the UKA group reported significantly less pain, a higher activity level, and greater satisfaction while performing several functional activities and could walk for a longer amount of time before stopping due to knee discomfort compared with those in the TKA group (p ≤ 0.038). In addition, a greater proportion of patients in the UKA than in the TKA group were "satisfied or very satisfied" with their knee replacement surgery at minimum 1-year follow-up (90% versus 81%; p = 0.043). CONCLUSIONS: With minimum 1-year follow-up, patients who underwent UKA reported significantly higher function, less pain, and a greater level of patient satisfaction than a radiographically and demographically matched TKA cohort. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Obesity-induced alterations in the gut microbiome in female mice fed a high-fat diet are antagonized by dietary supplementation with a novel, wax ester-rich, marine oil.

Dietary supplementation with calanus oil, a novel wax ester-rich marine oil, has been shown to reduce adiposity in high-fat diet (HFD)-induced obese mice. Current evidence suggests that obesity and its comorbidities are intrinsically linked with unfavorable changes in the intestinal microbiome. Thus, in line with its antiobesity effect, we hypothesized that dietary supplementation with calanus oil should counteract the obesity-related deleterious changes in the gut microbiota. Seven-week-old female C57bl/6J mice received an HFD for 12 weeks to induce obesity followed by 8-week supplementation with 2% calanus oil. For comparative reasons, another group of mice was treated with exenatide, an antiobesogenic glucagon-like peptide-1 receptor agonist. Mice fed normal chow diet or nonsupplemented HFD for 20 weeks served as lean and obese controls, respectively. 16S rRNA gene sequencing was performed on fecal samples from the colon. HFD increased the abundance of the Lactococcus and Leuconostoc genera relative to normal chow diet, whereas abundances of Allobaculum and Oscillospira were decreased. Supplementation with calanus oil led to an apparent overrepresentation of Lactobacillus and Streptococcus and underrepresentation of Bilophila. Exenatide prevented the HFD-induced increase in Lactococcus and caused a decrease in the abundance of Streptococcus compared to the HFD group. Thus, HFD altered the gut microbiota composition in an unhealthy direction by increasing the abundance of proinflammatory genera while reducing those considered health-promoting. These obesity-induced changes were antagonized by both calanus oil and exenatide.

Does Patellofemoral Disease Affect Outcomes in Contemporary Medial Fixed-Bearing Unicompartmental Knee Arthroplasty?

BACKGROUND: Pre-existing patellofemoral disease has traditionally been a contraindication to unicompartmental knee arthroplasty (UKA), as proposed by Kozinn and Scott. More recently, some propose that patellofemoral disease can be ignored in UKA; however, the supporting research is predominantly in mobile-bearing designs. The study purpose was to evaluate the effect of patellofemoral disease osteoarthritis severity on latest outcomes after fixed-bearing medial UKA. METHODS: A retrospective review of 147 consecutive medial fixed-bearing UKAs with minimum 1-year follow-up was performed. The medial and lateral patellofemoral compartments were graded according to the Kellgren & Lawrence grading system, Osteoarthritis Research Society International atlas, and intraoperative assessment performed using the Outerbridge classification. Prospectively collected University of California Los Angeles Activity Level, modern Knee Society pain and function scores, and Likert scale satisfaction were correlated with presence and severity of pre-existing patellofemoral disease. RESULTS: One hundred forty-three medial UKAs were analyzed with mean age, body mass index, and follow-up of 64.1 years, 30.7 kg/m2, and 24.0 months, respectively. No correlations were observed between patellofemoral disease severity and patient-reported outcome measures at latest follow-up or improvement scores for Kellgren & Lawrence grading system or Osteoarthritis Research Society International atlas (P ≥ .058). Improvement in activity level scores was significantly higher for patients with less patellar and trochlear chondral damage despite not reaching minimal clinically important difference of 2.0 (P ≤ .028). Regardless of patellofemoral disease severity, 93% of UKAs were satisfied or very satisfied. CONCLUSION: Clinical outcomes of fixed-bearing medial UKA were not adversely impacted by intraoperatively visualized or radiographically evaluated patellofemoral disease. Furthermore, long-term follow-up is warranted and caution should be used before considering patellofemoral disease as a contraindication for UKA.

Perioperative Infusion of Glucagon-Like Peptide-1 Prevents Insulin Resistance After Surgical Trauma in Female Pigs.

Insulin resistance is an independent negative predictor of outcome after elective surgery and increases mortality among surgical patients in intensive care. The incretin hormone glucagon-like peptide-1 (GLP-1) potentiates glucose-induced insulin release from the pancreas but may also increase insulin sensitivity in skeletal muscle and directly suppress hepatic glucose release. Here, we investigated whether a perioperative infusion of GLP-1 could counteract the development of insulin resistance after surgery. Pigs were randomly assigned to three groups; surgery/control, surgery/GLP-1, and sham/GLP-1. Both surgery groups underwent major abdominal surgery. Whole-body glucose disposal (WGD) and endogenous glucose release (EGR) were assessed preoperatively and postoperatively using D-[6,6-2H2]-glucose infusion in combination with hyperinsulinemic euglycemic step-clamping. In the surgery/control group, peripheral insulin sensitivity (i.e., WGD) was reduced by 44% relative to preoperative conditions, whereas the corresponding decline was only 9% for surgery/GLP-1 (P < 0.05). Hepatic insulin sensitivity (i.e., EGR) remained unchanged in the surgery/control group but was enhanced after GLP-1 infusion in both surgery and sham animals (40% and 104%, respectively, both P < 0.05). Intraoperative plasma glucose increased in surgery/control (∼20%) but remained unchanged in both groups receiving GLP-1 (P < 0.05). GLP-1 diminished an increase in postoperative glucagon levels but did not affect skeletal muscle glycogen or insulin signaling proteins after surgery. We show that GLP-1 improves intraoperative glycemic control, diminishes peripheral insulin resistance after surgery, and suppresses EGR. This study supports the use of GLP-1 to prevent development of postoperative insulin resistance.

Dietary Calanus oil recovers metabolic flexibility and rescues postischemic cardiac function in obese female mice.

The aim of this study was to find out whether dietary supplementation with Calanus oil (a novel marine oil) or infusion of exenatide (an incretin mimetic) could counteract obesity-induced alterations in myocardial metabolism and improve postischemic recovery of left ventricular (LV) function. Female C57bl/6J mice received high-fat diet (HFD, 45% energy from fat) for 12 wk followed by 8-wk feeding with nonsupplemented HFD, HFD supplemented with 2% Calanus oil, or HFD plus exenatide infusion (10 µg·kg-1·day-1). A lean control group was included, receiving normal chow throughout the whole period. Fatty acid and glucose oxidation was measured in ex vivo perfused hearts during baseline conditions, while LV function was assessed with an intraventricular fluid-filled balloon before and after 20 min of global ischemia. HFD-fed mice receiving Calanus oil or exenatide showed less intra-abdominal fat deposition than mice receiving nonsupplemented HFD. Both treatments prevented the HFD-induced decline in myocardial glucose oxidation. Somewhat surprising, recovery of LV function was apparently better in hearts from mice fed nonsupplemented HFD relative to hearts from mice fed normal chow. More importantly however, postischemic recovery of hearts from mice receiving HFD with Calanus oil was superior to that of mice receiving nonsupplemented HFD and mice receiving HFD with exenatide, as expressed by better pressure development, contractility, and relaxation properties. In summary, dietary Calanus oil and administration of exenatide counteracted obesity-induced derangements of myocardial metabolism. Calanus oil also protected the heart from ischemia, which could have implications for the prevention of obesity-related cardiac disease. NEW & NOTEWORTHY This article describes for the first time that dietary supplementation with a low amount (2%) of a novel marine oil (Calanus oil) in mice is able to prevent the overreliance of fatty acid oxidation for energy production during obesity. The same effect was observed with infusion of the incretin mimetic, exanatide. The improvement in myocardial metabolism in Calanus oil-treated mice was accompanied by a significantly better recovery of cardiac performance following ischemia-reperfusion. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/dietary-calanus-oil-energy-metabolism-and-cardiac-function/ .

Comparison of fluoroscopic techniques for assessment of femoral rotational alignment.

OBJECTIVES: Anatomic rotational reduction of diaphyseal femur fractures is essential in restoring limb mechanics. Errors in reproducing anteroposterior (AP) or lateral knee reference radiographs of the contralateral limb could result in inaccuracies during rotational reduction. The objective of this study was to examine whether fluoroscopic rotational variation can be observed with the same degree of precision with AP and lateral distal femur projections. METHODS: AP and lateral radiographs were obtained from intact knees of 7 cadaveric specimens using fluoroscopy. The lateral condylar width and coronal femoral width from the AP images and the posterior condylar offset and sagittal femoral width from the lateral images were measured by 3 reviewers. Interclass correlation coefficients (ICCs) among the 3 reviewers were calculated. The mean data from all reviewers were plotted against angle of rotation, and the slope (M) and regression of the line were then determined. RESULTS: ICCs were 0.997 (lateral) and 0.994 (AP), demonstrating excellent interobserver agreement. The mean (±SD) M value for lateral images was 0.016 ±â€Š0.001 and for AP images was 0.009 ±â€Š0.001 (P < .0001). The higher lateral M value represents a more appreciable difference in size of the measured segment for the same rotational change. CONCLUSIONS: The observed rotational change was 1.76 times greater on lateral images compared to AP images; thus, the lateral images may be more precise as a reference for rotation. The routine use of lateral knee radiographs to guide intraoperative rotational alignment of the femur may therefore be justified.

2,2,2-trichloroethanol activates a nonclassical potassium channel in cerebrovascular smooth muscle and dilates the middle cerebral artery.

Trichloroacetaldehyde monohydrate [chloral hydrate (CH)] is a sedative/hypnotic that increases cerebral blood flow (CBF), and its active metabolite 2,2,2-trichloroethanol (TCE) is an agonist for the nonclassical two-pore domain K(+) (K(2P)) channels TREK-1 and TRAAK. We sought to determine whether TCE dilates cerebral arteries in vitro by activating nonclassical K(+) channels. TCE dilated pressurized and perfused rat middle cerebral arteries (MCAs) in a manner consistent with activation of nonclassical K(+) channels. Dilation to TCE was inhibited by elevated external K(+) but not by an inhibitory cocktail (IC) of classical K(+) channel blockers. Patch-clamp electrophysiology revealed that, in the presence of the IC, TCE increased whole-cell currents and hyperpolarized the membrane potential of isolated MCA smooth muscle cells. Heating increased TCE-sensitive currents, indicating that the activated channel was thermosensitive. Immunofluorescence in sections of the rat MCA demonstrated that, like TREK-1, TRAAK is expressed in the smooth muscle of cerebral arteries. Isoflurane did not, however, dilate the MCA, suggesting that TREK-1 was not functional. These data indicate that TCE activated a nonclassical K(+) channel with the characteristics of TRAAK in rat MCA smooth-muscle cells. Stimulation of K(+) channels such as TRAAK in cerebral arteries may therefore explain in part how CH/TCE increases CBF.