Comprehensive Physiology最新文献

Glucagon-like peptide-1 (GLP-1), a hormone released from enteroendocrine cells in the distal small and large intestines in response to nutrients and other stimuli, not only controls eating and insulin release, but is also involved in drinking control as well as renal and cardiovascular functions. Moreover, GLP-1 functions as a central nervous system peptide transmitter, produced by preproglucagon (PPG) neurons in the hindbrain. Intestinal GLP-1 inhibits eating by activating vagal sensory neurons directly, via GLP-1 receptors (GLP-1Rs), but presumably also indirectly, by triggering the release of serotonin from enterochromaffin cells. GLP-1 enhances glucose-dependent insulin release via a vago-vagal reflex and by direct action on beta cells. Finally, intestinal GLP-1 acts on the kidneys to modulate electrolyte and water movements, and on the heart, where it provides numerous benefits, including anti-inflammatory, antiatherogenic, and vasodilatory effects, as well as protection against ischemia/reperfusion injury and arrhythmias. Hindbrain PPG neurons receive multiple inputs and project to many GLP-1R-expressing brain areas involved in reward, autonomic functions, and stress. PPG neuron-derived GLP-1 is involved in the termination of large meals and is implicated in the inhibition of water intake. This review details GLP-1's roles in these interconnected systems, highlighting recent findings and unresolved issues, and integrating them to discuss the physiological and pathological relevance of endogenous GLP-1 in coordinating these functions. As eating poses significant threats to metabolic, fluid, and immune homeostasis, the body needs mechanisms to mitigate these challenges while sustaining essential nutrient intake. Endogenous GLP-1 plays a crucial role in this "ingestive homeostasis."

Brown adipose tissue (BAT) and thermogenic beige fat within white adipose tissue (WAT), collectively known as adaptive thermogenic fat, dissipate energy as heat, offering promising therapeutic potential to combat obesity and metabolic disorders. The specific biological functions of these fat depots are determined by their unique interaction with the microenvironments, composed of immune cells, endothelial cells, pericytes, and nerve fibers. Immune cells residing in these depots play a key role in regulating energy expenditure and systemic energy homeostasis. The dynamic microenvironment of thermogenic fat depots is essential for maintaining tissue health and function. Immune cells infiltrate both BAT and beige WAT, contributing to their homeostasis and activation through intricate cellular communications. Emerging evidence underscores the importance of various immune cell populations in regulating thermogenic adipose tissue, though many remain undercharacterized. This review provides a comprehensive overview of the immune cells that regulate adaptive thermogenesis and their complex interactions within the adipose niche, highlighting their potential to influence metabolic health and contribute to therapeutic interventions for obesity and metabolic syndrome.

Idiopathic pulmonary fibrosis (IPF) is a chronic respiratory disease characterized by progressive scarring of the lung parenchyma. While two drugs have been approved by the US Food and Drug Administration (FDA) for IPF, median survival remains limited at 3 years, and the discovery of novel therapeutic targets is urgently needed. Recent studies indicate that immune cells play a critical role in regulating fibrosis. In this Mini Review, we discuss the recent literature focused on cells of the myeloid lineage that serve as key agents of pathologic interorgan communication in fibrosis. These cells are recruited from the bone marrow and have been found to be key drivers of the fibrotic process in the lung.

Psychological stress has emerged as a critical risk factor for cardiovascular disease, especially in women. While female participation in clinical research has improved, sex-specific data analysis and reporting often remain inadequate, limiting our ability to draw definitive conclusions for women. Conversely, preclinical studies consistently demonstrate adverse effects of stress on female health, yet the molecular mechanisms underlying this association remain elusive. Evidence suggests that female IHD pathogenesis is more complex than in males, involving multiple factors, including inflammation, contractile dysfunction, bioenergetic impairment, and remodeling. However, many of these mechanisms are primarily derived from male studies, and molecular investigations in female models are limited, hindering our understanding of the underlying biological pathways. This is particularly concerning given the increasing prevalence of ischemic heart disease in postmenopausal women. In order to fully elucidate the impact of stress on female cardiac health and develop targeted interventions, further preclinical research on female models is essential.

Recent advances in our ability to collect and process information, particularly through artificial intelligence, opens up some exciting possibilities for understanding interorgan communication and treating conditions that arise from that communication breaking down. We describe a vision of a digital twin of interorgan communication that will give us a testbed for virtually researching, teaching and searching treatments, greatly increasing our capabilities to understand and manage the complex interactions in our bodies.

Humans are perhaps evolutionarily engineered to get deeply addicted to sugar, as it not only provides energy but also helps in storing fats, which helps in survival during starvation. Additionally, sugars (glucose and fructose) stimulate the feel-good factor, as they trigger the secretion of serotonin and dopamine in the brain, associated with the reward sensation, uplifting the mood in general. However, when consumed in excess, it contributes to energy imbalance, weight gain, and obesity, leading to the onset of a complex metabolic disorder, generally referred to as diabetes. Type 2 diabetes mellitus (T2DM) is one of the most prevalent forms of diabetes, nearly affecting all age groups. T2DM is clinically diagnosed with a cardinal sign of chronic hyperglycemia (excessive sugar in the blood). Chronic hyperglycemia, coupled with dysfunctions of pancreatic β-cells, insulin resistance, and immune inflammation, further exacerbate the pathology of T2DM. Uncontrolled T2DM, a major public health concern, also contributes significantly toward the onset and progression of several micro- and macrovascular diseases, such as diabetic retinopathy, nephropathy, neuropathy, atherosclerosis, and cardiovascular diseases, including cancer. The current review discusses the epidemiology, causative factors, pathophysiology, and associated comorbidities, including the existing and emerging therapies related to T2DM. It also provides a future roadmap for alternative drug discovery for the management of T2DM.

Obesity rates have surged to pandemic levels, placing tremendous burden on our society. This chronic and complex disease is related to the development of many life-threatening illnesses including cardiovascular diseases. Hypertension caused by obesity increases the risk for cardiovascular mortality and morbidity by promoting stroke, myocardial infarction, congestive heart failure, and end-stage renal disease. Overwhelming evidence supports neural origins for obesity-induced hypertension and pinpoints the adipose-derived hormone, leptin, and the sympathetic nervous system as major causal factors. Hyperleptinemia in obesity is associated with selective leptin resistance where leptin's renal sympathoexcitatory and pressor effects are preserved while the metabolic actions are impaired. Understanding the mechanisms driving this phenomenon is critical for developing effective therapeutics. This review describes the neural mechanisms of obesity-induced hypertension with a focus on the molecular and neuronal substrates of leptin action.

The evolution of mechanisms for terrestrial locomotion has resulted in multi-segmented limbs that allow navigation on irregular terrains, changing of direction, manipulation of external objects, and control over the mechanical properties of limbs important for interaction with the environment, with corresponding changes in neural pathways in the spinal cord. This article is focused on the organization of these pathways, their interactions with the musculoskeletal system, and the integration of these neuromechanical circuits with supraspinal mechanisms to control limb impedance. It is argued that neural pathways from muscle spindles and Golgi tendon organs form a distributive impedance controller in the spinal cord that controls limb impedance and coordination during responses to external disturbances. These pathways include both monosynaptic and polysynaptic components. Autogenic, monosynaptic pathways serve to control the spring-like properties of muscles preserving the nonlinear relationship between stiffness and force. Intermuscular monosynaptic pathways compensate for inertial disparities between the inertial properties of limb segments and help to control inertial coupling between joints and axes of rotation. Reciprocal inhibition controls joint stiffness in conjunction with feedforward cocontraction commands. Excitatory force feedback becomes operational during locomotion and increases muscular stiffness to accommodate the higher inertial loads. Inhibitory force feedback is widely distributed among muscles. It is integrated with excitatory pathways from muscle spindles and Golgi tendon organs to determine limb stiffness and interjoint coordination during interactions with the environment. The intermuscular distribution of force feedback is variable and serves to modulate limb stiffness to meet the physical demands of different motor tasks. © 2024 American Physiological Society. Compr Physiol 14:5789-5838, 2024.

The proper development and function of the placenta are essential for the success of pregnancy and the well-being of both the fetus and the mother. Placental vascular function facilitates efficient fetal development during pregnancy by ensuring adequate gas exchange with low vascular resistance. This review focuses on how placental vascular function can be compromised in the pregnancy pathology preeclampsia, and conversely, how placental vascular dysfunction might contribute to this condition. While the maternal endothelium is widely recognized as a key focus in preeclampsia research, this review emphasizes the importance of understanding how this condition affects the development and function of the fetal placental vasculature. The placental vascular bed, consisting of microvasculature and macrovasculature, is discussed in detail, as well as structural and functional changes associated with preeclampsia. The complexity of placental vascular reactivity and function, its mediators, its impact on placental exchange and blood distribution, and how these factors are most affected in early-onset preeclampsia are further explored. These factors include foremost lipoproteins and their cargo, oxygen levels and oxidative stress, biomechanics, and shear stress. Challenges in studying placental pathophysiology are discussed, highlighting the necessity of innovative research methodologies, including ex vivo experiments, in vivo imaging tools, and computational modeling. Finally, an outlook on the potential of drug interventions targeting the placental endothelium to improve placental vascular function in preeclampsia is provided. Overall, this review highlights the need for further research and the development of models and tools to better understand and address the challenges posed by preeclampsia and its effects on placental vascular function to improve short- and long-term outcomes for the offspring of preeclamptic pregnancies. © 2024 American Physiological Society. Compr Physiol 14:5763-5787, 2024.