Respiratory effects of oral mitragynine and oxycodone in a rodent model.

RATIONALE: Kratom derives from Mitragyna speciosa (Korth.), a tropical tree in the genus Mitragyna (Rubiaceae) that also includes the coffee tree. Kratom leaf powders, tea-like decoctions, and commercial extracts are taken orally, primarily for health and well-being by millions of people globally. Others take kratom to eliminate opioid use for analgesia and manage opioid withdrawal and use disorder. There is debate over the possible respiratory depressant overdose risk of the primary active alkaloid, mitragynine, a partial µ-opioid receptor agonist, that does not signal through ß-arrestin, the primary opioid respiratory depressant pathway. OBJECTIVES: Compare the respiratory effects of oral mitragynine to oral oxycodone in rats with the study design previously published by US Food and Drug Administration (FDA) scientists for evaluating the respiratory effects of opioids (Xu et al., Toxicol Rep 7:188-197, 2020). METHODS: Blood gases, observable signs, and mitragynine pharmacokinetics were assessed for 12 h after 20, 40, 80, 240, and 400 mg/kg oral mitragynine isolate and 6.75, 60, and 150 mg/kg oral oxycodone hydrochloride. FINDINGS: Oxycodone administration produced significant dose-related respiratory depressant effects and pronounced sedation with one death each at 60 and 150 mg/kg. Mitragynine did not yield significant dose-related respiratory depressant or life-threatening effects. Sedative-like effects, milder than produced by oxycodone, were evident at the highest mitragynine dose. Maximum oxycodone and mitragynine plasma concentrations were dose related. CONCLUSIONS: Consistent with mitragynine's pharmacology that includes partial µ-opioid receptor agonism with little recruitment of the respiratory depressant activating ß-arrestin pathway, mitragynine produced no evidence of respiratory depression at doses many times higher than known to be taken by humans.

High-fat diet induced central adiposity (visceral fat) is associated with increased fibrosis and decreased immune cellularity of the mesenteric lymph node in mice.

PURPOSE: Accumulation of visceral, but not subcutaneous, adipose tissue is highly associated with metabolic disease. Inflammation inciting from adipose tissue is commonly associated with metabolic disease risk and comorbidities. However, constituents of the immune system, lymph nodes, embedded within these adipose depots remain under-investigated. We hypothesize that, lymph nodes are inherently distinct and differentially respond to diet-induced obesity much like the adipose depots they reside in. METHODS: Adipose tissue and lymph nodes were collected from the visceral and inguinal depots of male mice fed 13 weeks of standard CHOW or high fat diet (HFD). Immune cells were isolated from tissues, counted and characterized by flow cytometry or plated for proliferative capacity following Concanavalin A stimulation. Lymph node size and fibrosis area were also characterized. RESULTS: In HFD fed mice visceral adipose tissue accumulation was associated with significant enlargement of the lymph node encased within. The subcutaneous lymph node did not change. Compared with mice fed CHOW for 13 weeks, mice fed HFD had a decline in immune cell populations and immune cell proliferative ability, as well as, exacerbated fibrosis accumulation, within the visceral, but not subcutaneous, lymph node. CONCLUSIONS: Obesity-induced chronic low-grade inflammation is associated with impaired immunity and increased susceptibility to disease. Excessive visceral adiposity and associated inflammation driven by diet likely leads to obesity-induced immune suppression by way of lymph node/lymphatic system pathophysiology.

Adipose tissue extrinsic factor: Obesity-induced inflammation and the role of the visceral lymph node.

Obesity-related adverse health consequences occur predominately in individuals with upper body fat distribution commonly associated with increased central adiposity. Visceral adipose tissue accumulation is described to be the greatest driver of obesity-induced inflammation, however evidence also supports that the intestines fundamentally contribute to the development of obesity-induced metabolic disease. The visceral adipose depot shares the same vasculature and lymph drainage as the small intestine. We hypothesize that the visceral lymph node, which drains adipose tissue and the gastrointestinal tract, is central to the exacerbation of systemic pro-inflammation. Male C57BL/6 mice were fed CHOW or high fat diet (HFD) for 7 weeks. At termination the mesenteric depot, visceral lymph node and ileum, jejunum and Peyer's patches were collected. Cytokine concentration was determined in adipose tissue whereas immune cell populations where investigated in the visceral lymph node and intestinal segments by flow cytometry. Visceral adipose tissue and the gastrointestinal tract mutually influence immune cells enclosed within the visceral lymph node. HFD increased visceral lymph node immune cell number. This likely resulted from 1.) an increase in immune cells migration from the small intestines likely from activated dendritic cells that travel to the lymph node and 2.) cytokine effluent from visceral adipose tissue that promoted expansion, survival and retention of pro-inflammatory immune cells. Overall, the visceral lymph node, the immune nexus of visceral adipose tissue and the small intestines, likely plays a fundamental role in exacerbation of systemic pro-inflammation by HFD-induced obesity. The research of Tim Bartness greatly enhanced the understanding of adipose tissue regulation. Studies from his laboratory significantly contributed to our awareness of extrinsic factors that influence body fatness levels. Specifically, the work he produced eloquently demonstrated that adipose tissue was more complex than an insulating storage center; it was connected to our brains via the sympathetic and sensory nervous system. Mapping studies demonstrated that adipose tissue both receives and sends information to the brain. Further, his lab demonstrated that nervous system connections contributed to lipolysis, thermogenesis and adipocyte proliferation and growth. The work of Tim Bartness will continue to influence adipose tissue research. As such, Tim Bartness directly inspired the following research. Adipose tissue extrinsic factors are not limited to the peripheral nervous system. The lymphatic system is an additional extrinsic factor that cross talks with adipose tissue, however its role in this context is under emphasized. Here we begin to elucidate how the lymphatic system may contribute to the comorbidities associated with visceral adipose tissue accumulation.

Adipose tissue: an endocrine organ playing a role in metabolic regulation.

Adipose tissue is a complex endocrine organ with an intricate role in whole body homeostasis. Beyond storing energy, adipose tissue is fundamental in numerous processes including, but not limited to, metabolism, food intake and immune cell function. Adipokines and cytokines are the signaling factors from adipose tissue. These factors play a role in maintaining health, but are also candidates for pathologies associated with obesity. Indeed excessive adiposity causes dysregulation of these factors which negatively affect health and contribute to numerous obesity-induced co-morbidities. In particular, adipokines are fundamental in regulation of glucose homeostasis and insulin signaling, thus aberrant production of these adipose derived hormones correlates with the development and progression of type 2 diabetes. Therefore, elucidation of adipose regulation is crucial for understanding the pathophysiological basis of obesity and metabolic diseases such as type 2 diabetes. In the present review, we summarize current data on the relation between adipokines and adipose depot derived cytokines in the maintenance of glucose homeostasis. Specifically, physiological and molecular functions of several adipokines are defined with particular focus on interactions within the insulin-signaling pathway and subsequent regulation of glucose uptake in both standard and obesity-induced dysregulated conditions. This same relation will be discussed for cytokines and inflammation as well.

Crosstalk between Microbiota-Derived Short-Chain Fatty Acids and Intestinal Epithelial HIF Augments Tissue Barrier Function.

Interactions between the microbiota and distal gut are fundamental determinants of human health. Such interactions are concentrated at the colonic mucosa and provide energy for the host epithelium through the production of the short-chain fatty acid butyrate. We sought to determine the role of epithelial butyrate metabolism in establishing the austere oxygenation profile of the distal gut. Bacteria-derived butyrate affects epithelial O2 consumption and results in stabilization of hypoxia-inducible factor (HIF), a transcription factor coordinating barrier protection. Antibiotic-mediated depletion of the microbiota reduces colonic butyrate and HIF expression, both of which are restored by butyrate supplementation. Additionally, germ-free mice exhibit diminished retention of O2-sensitive dyes and decreased stabilized HIF. Furthermore, the influences of butyrate are lost in cells lacking HIF, thus linking butyrate metabolism to stabilized HIF and barrier function. This work highlights a mechanism where host-microbe interactions augment barrier function in the distal gut.

Adipose tissue, obesity and adipokines: role in cancer promotion.

Adipose tissue is a complex organ with endocrine, metabolic and immune regulatory roles. Adipose depots have been characterized to release several adipocytokines that work locally in an autocrine and paracrine fashion or peripherally in an endocrine fashion. Adipocyte hypertrophy and excessive adipose tissue accumulation, as occurs during obesity, dysregulates the microenvironment within adipose depots and systemically alters peripheral tissue metabolism. The term "adiposopathy" is used to describe this promotion of pathogenic adipocytes and associated adipose - elated disorders. Numerous epidemiological studies confirm an association between obesity and various cancer forms. Proposed mechanisms that link obesity/adiposity to high cancer risk and mortality include, but are not limited to, obesity-related insulin resistance, hyperinsulinemia, sustained hyperglycemia, glucose intolerance, oxidative stress, inflammation and/or adipocktokine production. Several epidemiological studies have demonstrated a relationship between specific circulating adipocytokines and cancer risk. The aim of this review is to define the function, in normal weight and obesity states, of well-characterized and novel adipokines including leptin, adiponectin, apelin, visfatin, resistin, chemerin, omentin, nesfatin and vaspin and summarize the data that relates their dysfunction, whether associated or direct effects, to specific cancer outcomes. Overall research suggests most adipokines promote cancer cell progression via enhancement of cell proliferation and migration, inflammation and anti-apoptosis pathways, which subsequently can prompt cancer metastasis. Further research and longitudinal studies are needed to define the specific independent and additive roles of adipokines in cancer progression and reoccurrence.

Detrimental and protective fat: body fat distribution and its relation to metabolic disease.

Obesity is linked to numerous comorbidities that include, but are not limited to, glucose intolerance, insulin resistance, dyslipidemia, and cardiovascular disease. Current evidence suggests, however, obesity itself is not an exclusive predictor of metabolic dysregulation but rather adipose tissue distribution. Obesity-related adverse health consequences occur predominately in individuals with upper body fat accumulation, the detrimental distribution, commonly associated with visceral obesity. Increased lower body subcutaneous adipose tissue, however, is associated with a reduced risk of obesity-induced metabolic dysregulation and even enhanced insulin sensitivity, thus, storage in this region is considered protective. The proposed mechanisms that causally relate the differential outcomes of adipose tissue distribution are often attributed to location and/or adipocyte regulation. Visceral adipose tissue effluent to the portal vein drains into the liver where hepatocytes are directly exposed to its metabolites and secretory products, whereas the subcutaneous adipose tissue drains systemically. Adipose depots are also inherently different in numerous ways such as adipokine release, immunity response and regulation, lipid turnover, rate of cell growth and death, and response to stress and sex hormones. Proximal extrinsic factors also play a role in the differential drive between adipose tissue depots. This review focuses on the deleterious mechanisms postulated to drive the differential metabolic response between central and lower body adipose tissue distribution.