The past two decades have seen an explosive increase of obesity rates worldwide, with more than one billion adults overweight and 300 million of them obese. Obesity and its associated complications have become leading causes of morbidity and mortality in the United States and major contributing factors to the rising costs of national health care. The pathophysiology of obesity and type 2 diabetes in rodents and humans is characterized by low-grade inflammation and chronic activation of immune pathways in adipose tissue and liver. The CD40 receptor and its ligand, CD40L, initiate immune cell signaling promoting inflammation, but conflicting data on CD40L-null mice confound its role in obesity-associated insulin resistance. A clear understanding of how CD40 and its ligand communicate to regulate and sustain the inflammatory environment of obesity is lacking. Here we demonstrate that CD40 receptor deficient mice on a high-fat diet display the expected decrease in hepatic cytokine levels, but paradoxically exhibit liver steatosis, insulin resistance and glucose intolerance compared with their age-matched wild-type controls. Hyperinsulinemic-euglycemic clamp studies also demonstrated insulin resistance in glucose utilization by the CD40-null mice compared with wild-type mice. In contrast to liver, visceral adipose tissue in CD40 deficient animals harbors elevated cytokine levels and infiltration of inflammatory cells, particularly macrophages and CD8+ effector T cells. In addition, ex vivo explants of epididymal adipose tissue from CD40-null mice display elevated basal and isoproterenol-stimulated lipolysis, suggesting a potential increase of lipid efflux from visceral fat to the liver. These findings reveal that 1) CD40-null mice represent an unusual model of hepatic steatosis with reduced hepatic inflammation, and 2) CD40 unexpectedly functions in adipose tissue to attenuate the chronic inflammation associated with obesity, thereby protecting against hepatic steatosis.

Systemic glucose regulation is essential for human survival as low or chronically high glucose levels can be detrimental to the health of an individual. Glucose levels are highly regulated via inter-organ communication networks that alter metabolic function to maintain euglycemia. For example, when nutrient levels are low, pancreatic α-cells secrete glucagon, which signals to the liver to promote glycogen breakdown and glucose production. In times of excess nutrient intake, pancreatic β-cells release insulin. Insulin signals to the liver to suppress hepatic glucose production, and signals to the adipose tissue and the skeletal muscle to take up excess glucose via insulin-regulated glucose transporters. Defects in this inter-organ communication network including insulin resistance can result in glucose deregulation and ultimately the onset of type-2 diabetes (T2D). To identify novel regulators of insulin-mediated glucose transport, our laboratory performed an siRNA-mediated gene-silencing screen in cultured adipocytes and measured insulin-mediated glucose transport. Gene silencing of Mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4), a Sterile-20-related serine/threonine protein kinase, enhanced insulin-stimulated glucose transport, suggesting Map4k4 inhibits insulin action and glucose transport. Thus, for the first part of my thesis, I explore the role of Map4k4 in cultured adipose cells and show that Map4k4 also represses lipid synthesis independent of its effects on glucose transport. Map4k4 inhibits lipid synthesis in a Mechanistic target of rapamycin complex 1 (mTORC1)- and Sterol regulatory element-binding transcription factor 1 (Srebp-1)-dependent mechanism and not via a c-Jun NH2-terminal kinase (Jnk)-dependent mechanism. For the second part of my thesis, I explore the metabolic function of Map4k4 in vivo. Using mice with loxP sites flanking the Map4k4 allele and a ubiquitously expressed tamoxifen-activated Cre, we inducibly ablated Map4k4 expression in adult mice and found significant improvements in metabolic health indicated by improved fasting glucose and whole-body insulin action. To assess the role of Map4k4 in specific metabolic tissues responsible for systemic glucose regulation, we employed tissue-specific knockout mice to deplete Map4k4 in adipose tissue using an adiponectin-cre transgene, liver using an albumin-cre transgene, and skeletal muscle using a Myf5-cre transgene. Ablation of Map4k4 expression in adipose tissue or liver had no impact on whole body glucose homeostasis or insulin resistance. However, we surprisingly found that Map4k4 depletion in Myf5-positive tissues, which include skeletal muscles, largely recapitulates the metabolic phenotypes observed in systemic Map4k4 knockout mice, restoring obesity-induced glucose intolerance and insulin resistance. Furthermore these metabolic changes were associated with enhanced insulin signaling to Akt in the visceral adipose tissue, a tissue that is nearly devoid of Myf5-positive cells and does not display changes in Map4k4 expression. Thus, these results indicate that Map4k4 in Myf5-positive cells, most likely skeletal muscle cells, inhibits whole-body insulin action and these effects may be mediated via an indirect effect on the visceral adipose tissue. The results presented here provide evidence for Map4k4 as a potential therapeutic target for the treatment of insulin resistance and T2D.

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The goal of this long-term study was to better understand the reproductive biology of the female bottlenose dolphin (Tursiops truncatus) and provide a hypothesis for how dolphins may communicate reproductive readiness to one another. Utilizing conditioned dolphins in aquaria, this dissertation examined several previously unknown aspects of dolphin reproduction, including ovarian follicular dynamics during the luteinizing hormone surge, urinary prolactin levels, estrus behavior, vaginal fluid arboriform arrangement, in-situ vaginal and cervical anatomy during estrus, reversed-phase high-performance liquid chromatography (RP-HPLC) of urine samples to identify proteins and peptides that may be used in chemical communication, and a review and anatomical analysis of dolphin vibrassal crypts. The diffusely seasonal dolphin estrous cycle is not controlled by photoperiod and has a 10-day follicular and 20-day luteal phase. A brief ovulatory LH surge is followed by ovulation within 48 hours. An ethogram of 20 reproductive behaviors was developed, and all occurrences of reproductive behavior were analyzed during conceptive estrous cycles. A novel form of standing heat estrus, termed immobility, was observed, and estrus dolphins displayed genital nuzzling, active and passive mounting with other females, and an increase of standing heat intensity as LH levels rose. Prolactin plays a role in pregnancy maintenance, mammary development, allo-mothering behavior, lactation, and lactational anestrus. Dolphins are similar to sows where weaning causes a return to estrus, and in the boar effect, where days to ovulation are shortened in the presence of a mature male. Dolphin vaginal fluid showed crystallization arrangements with large open mesh patterns, conducive to sperm transport, during the estrogenic follicular phase, and closed mesh during the luteal phase. RP-HPLC analysis revealed that urine contained large amounts of peptides and proteins with peaks that change throughout the estrous cycle and with changes in social grouping. Remnant vibrissae from dolphin follicular crypts were sectioned, and it was hypothesized that trigeminal nerve endings could act similarly to those found in the nasal mucosa of terrestrial species and respond to chemical stimuli. This study provides new data to better understand the reproductive biology of a holaquatic mammal.

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Background: One of the most prevalent diseases in the world, type 2 diabetes mellitus is rising every year. Self-care refers to controlling one's own illness to prevent future complications. The nurses' work is oriented on a person-centered approach to inform, promote, encourage, and support the patient to maintain good health in consideration of their circumstances. Aim: The aim of this literature study was to describe persons' experiences with self-care of type 2 diabetes mellitus.   Method: A literature study based on qualitative scientific articles which were retrieved from PubMed and CINAHL. A thematic analysis was used to analyze the articles. The study's objective was accomplished.  Results: The two main themes were identified. Experiences that affect self-care and Experiences of self-care’s impact on life.  Conclusion: Self-care is influenced by several factors such as knowledge, experience of support and control. The self-care and adaptation required for these affects the lives of people with type 2 Diabetes. Nurses have a key role in patients' self-care by helping people manage self-care. / Bakgrund: En av de vanligaste sjukdomarna i världen, typ 2 diabetes mellitus ökar varje år. Egenvård avser att kontrollera sin egen sjukdom för att förhindra framtida komplikationer. På grund av detta är sjuksköterskornas arbete inriktat på ett personcentrerat förhållningssätt för att informera, främja, uppmuntra och stödja patienten att bibehålla en god hälsa med hänsyn till sina omständigheter. Syfte: Syftet med denna litteraturstudie var att beskriva personers erfarenheter av egenvård av typ 2 diabetes mellitus. Metod: En litteraturstudie baserad på kvalitativa vetenskapliga artiklar som hämtats från PubMed och CINAHL. En tematisk analys användes för att analysera artiklarna. Studiens mål uppnåddes. Resultat: Två huvudteman identifierades. Erfarenheter som påverkar egenvården och erfarenheter av egenvårdens påverkan på livet. Slutsats: Egenvården påverkar flera faktorer såsom kunskap, erfarenhet av stöd och kontroll. Egenvården och anpassningen som krävs för dessa påverkar livet hos personer med typ 2 diabetes mellitus. Sjuksköterska har en nyckelroll i patienters egenvård genom att hjälpa personer att hantera egenvården.