Journal: Trends in endocrinology and metabolism: TEM
The negative impact of consuming sugar-sweetened beverages on weight and other health outcomes has been increasingly recognized; therefore, many people have turned to high-intensity sweeteners like aspartame, sucralose, and saccharin as a way to reduce the risk of these consequences. However, accumulating evidence suggests that frequent consumers of these sugar substitutes may also be at increased risk of excessive weight gain, metabolic syndrome, type 2 diabetes, and cardiovascular disease. This paper discusses these findings and considers the hypothesis that consuming sweet-tasting but noncaloric or reduced-calorie food and beverages interferes with learned responses that normally contribute to glucose and energy homeostasis. Because of this interference, frequent consumption of high-intensity sweeteners may have the counterintuitive effect of inducing metabolic derangements.
Overnutrition-induced diseases such as obesity and type 2 diabetes (T2D) involve neural dysregulation of metabolic physiology. Recently, interdisciplinary research in neuroscience and immunology has linked overnutrition to a non-classical onset of inflammation in the brain, particularly in the hypothalamus. This neuroinflammation impairs central regulatory pathways of energy balance and nutrient metabolism, and leads to obesity, diabetes, and cardiovascular complications. This review describes recent findings on the roles of overnutrition-induced hypothalamic inflammation in neurodegeneration and defective adult neurogenesis, as well as in impaired neural stem cell regeneration, and their relevance to obesity and related diseases. In addition, commonalities in terms of neuroinflammation between neurodegenerative diseases and overnutrition-induced metabolic diseases are discussed. Targeting neuroinflammation and neurodegeneration will provide promising approaches for treating obesity and other overnutrition-related diseases.
Coffee is the most frequently consumed caffeine-containing beverage. The caffeine in coffee is a bioactive compound with stimulatory effects on the central nervous system and a positive effect on long-term memory. Although coffee consumption has been historically linked to adverse health effects, new research indicates that coffee consumption may be beneficial. Here we discuss the impact of coffee and caffeine on health and bring attention to the changing caffeine landscape that includes new caffeine-containing energy drinks and supplements, often targeting children and adolescents.
Brown adipocytes are specialized cells capable of undergoing thermogenesis, a phenomenon regulated by the sympathetic nervous system, due to the presence of uncoupling protein 1 (UCP1). The recent demonstrations of their presence in adult humans, and the discovery that brown adipocytes can be derived from distinct precursors and express specific genes depending on their anatomic location, have sparked intense interest in enhancing the current understanding of their biology and relevance to human energy homeostasis. We provide an overview of the latest advances related to the developmental origins of brown adipocytes, discuss their regulation and function in both rodents and humans, and offer a critical perspective on the relevance of brown adipocyte-mediated thermogenesis in human physiology.
This review summarizes how fatty acid (FA) oxidation is regulated in skeletal muscle during exercise. From the available evidence it seems that acetyl-CoA availability in the mitochondrial matrix adjusts FA oxidation to exercise intensity and duration. This is executed at the step of mitochondrial fatty acyl import, as the extent of acetyl group sequestration by carnitine determines the availability of carnitine for the carnitine palmitoyltransferase 1 (CPT1) reaction. The rate of glycolysis seems therefore to be central to the amount of β-oxidation-derived acetyl-CoA that is oxidized in the tricarboxylic acid (TCA) cycle. FA oxidation during exercise is also determined by FA availability to mitochondria, dependent on trans-sarcolemmal FA uptake via cluster of differentiation 36/SR-B2 (CD36) and FAs mobilized from myocellular lipid droplets.
Cell replacement therapy is a promising method to restore pancreatic β cell function and cure diabetes. Distantly related cells (fibroblasts, keratinocytes, and muscle cells) and developmentally related cells (hepatocytes, gastrointestinal, and pancreatic exocrine cells) have been successfully reprogrammed into β cells in vitro and in vivo. However, while some reprogrammed β cells bear similarities to bona fide β cells, others do not develop into fully functional β cells. Here we review various strategies currently used for β cell reprogramming, including ectopic expression of specific transcription factors associated with islet development, repression of maintenance factors of host cells, regulation of epigenetic modifications, and microenvironmental changes. Development of simple and efficient reprogramming methods is a key priority for developing fully functional β cells suitable for cell replacement therapy.
Diabetes is rapidly emerging as one of the biggest health concerns worldwide, with profound implications for disability, mortality, and costs. This suddenly escalating rate of diabetes correlates with global industrialization and the production of plastics, pesticides, synthetic fertilizers, electronic waste, and food additives that release endocrine-disrupting chemicals (EDCs) into the environment and the food chain. Emerging evidence indicates an association between exposure of EDCs and diabetes. In humans, these chemicals are also metabolized by the gut microbiota and thereby their toxicodynamics are altered. In this review we highlight studies that focus on the role of gut microbiota in EDC-induced hyperglycemia and dysregulated glucose homeostasis. We also discuss the translational implications of understanding EDC-microbiota interactions for the diagnosis and treatment of diabetes.
Cholecystokinin (CCK) regulates appetite and reduces food intake by activating the type 1 CCK receptor (CCK1R). Attempts to develop CCK1R agonists for obesity have yielded active agents that have not reached clinical practice. Here we discuss why, along with new strategies to target CCK1R more effectively. We examine signaling events and the possibility of developing agents that exhibit ligand-directed bias, to dissociate satiety activity from undesirable side effects. Potential allosteric sites of modulation are also discussed, along with desired properties of a positive allosteric modulator (PAM) without intrinsic agonist action as another strategy to treat obesity. These new types of CCK1R-active drugs could be useful as standalone agents or as part of a rational drug combination for management of obesity.
Inflammatory bowel disease (IBD) is a chronic disorder characterized by inflammation of the gastrointestinal tract and an immune-mediated attack against the commensal microbiota. Vitamin D is an essential vitamin that not only promotes calcium and phosphate absorption but also regulates immune function. The active form of vitamin D [1,25(OH)2D] has been shown to suppress symptoms of IBD by inhibiting T cell responses. Host protection from gastrointestinal infection depends on T cells. Paradoxically, vitamin D deficiency increases susceptibility to IBD and gastrointestinal infection. Here we review the roles of vitamin D in immune cells using a kinetic model of the vitamin D-mediated effects on infection to explain the sometimes paradoxical effects of vitamin D on gastrointestinal immunity.
Food intake and energy expenditure are the typical determinants of body weight. Yet, recent observations underscore that a third and often-neglected factor, fecal energy loss, can influence energy balance. Here, we explore how macronutrient excretion modulates human energy homeostasis and highlight its potential impact on the propensity to gain weight.