scholarly journals Role of the saturated fatty acid palmitate in the interconnected hypothalamic control of energy homeostasis and biological rhythms

2018 ◽  
Vol 315 (2) ◽  
pp. E133-E140 ◽  
Author(s):  
Erika K. Tse ◽  
Ashkan Salehi ◽  
Matthew N. Clemenzi ◽  
Denise D. Belsham
Keyword(s):  
Circadian Rhythms ◽  
Cell Lines ◽  
High Fat Diet ◽  
Energy Homeostasis ◽  
Clock Gene ◽  
Neuronal Cell ◽  
Whole Body ◽  
High Fat ◽  
Neuronal Cell Lines

The brain, specifically the hypothalamus, controls whole body energy and glucose homeostasis through neurons that synthesize specific neuropeptides, whereas hypothalamic dysfunction is linked directly to insulin resistance, obesity, and type 2 diabetes mellitus. Nutrient excess, through overconsumption of a Western or high-fat diet, exposes the hypothalamus to high levels of free fatty acids, which induces neuroinflammation, endoplasmic reticulum stress, and dysregulation of neuropeptide synthesis. Furthermore, exposure to a high-fat diet also disrupts normal circadian rhythms, and conversely, clock gene knockout models have symptoms of metabolic disorders. While whole brain/animal studies have provided phenotypic end points and important clues to the genes involved, there are still major gaps in our understanding of the intracellular pathways and neuron-specific components that ultimately control circadian rhythms and energy homeostasis. Because of its complexity and heterogeneous nature, containing a diverse mix cell types, it is difficult to dissect the critical hypothalamic components involved in these processes. Of significance, we have the capacity to study these individual components using an extensive collection of both embryonic- and adult-derived, immortalized hypothalamic neuronal cell lines from rodents. These defined neuronal cell lines have been used to examine the impact of nutrient excess, such as palmitate, on circadian rhythms and neuroendocrine signaling pathways, as well as changes in vital neuropeptides, leading to the development of neuronal inflammation; the role of proinflammatory molecules in this process; and ultimately, restoration of normal signaling, clock gene expression, and neuropeptide synthesis in disrupted states by beneficial anti-inflammatory compounds in defined hypothalamic neurons.

scholarly journals Endothelial-specific FoxO1 depletion prevents obesity-related disorders by increasing vascular metabolism and growth

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Martina Rudnicki ◽  
Ghoncheh Abdifarkosh ◽  
Emmanuel Nwadozi ◽  
Sofhia V Ramos ◽  
Armin Makki ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
High Fat Diet ◽  
Energy Homeostasis ◽  
Tissue Expansion ◽  
Tissue Level ◽  
Whole Body ◽  
Vascular Density ◽  
High Fat ◽  
Fasting Glycemia ◽  
Underlying Mechanisms

Impaired angiogenesis is a hallmark of metabolically dysfunctional adipose tissue in obesity. However, the underlying mechanisms restricting angiogenesis within this context remain ill-defined. Here, we demonstrate that induced endothelial-specific depletion of the transcription factor Forkhead Box O1 (FoxO1) in male mice led to increased vascular density in adipose tissue. Upon high-fat diet feeding, endothelial cell FoxO1-deficient mice exhibited even greater vascular remodeling in the visceral adipose depot, which was paralleled with a healthier adipose tissue expansion, higher glucose tolerance and lower fasting glycemia concomitant with enhanced lactate levels. Mechanistically, FoxO1 depletion increased endothelial proliferative and glycolytic capacities by upregulating the expression of glycolytic markers, which may account for the improvements at the tissue level ultimately impacting whole-body glucose metabolism. Altogether, these findings reveal the pivotal role of FoxO1 in controlling endothelial metabolic and angiogenic adaptations in response to high-fat diet and a contribution of the endothelium to whole-body energy homeostasis.

scholarly journals ANGPTL4 from adipose, but not liver, is responsible for regulating plasma triglyceride partitioning

2020 ◽  
Author(s):  
Kathryn M. Spitler ◽  
Shwetha K. Shetty ◽  
Emily M. Cushing ◽  
Kelli L. Sylvers-Davie ◽  
Brandon S.J. Davies
Keyword(s):  
Metabolic Disease ◽  
Insulin Sensitivity ◽  
Glucose Homeostasis ◽  
High Fat Diet ◽  
Plasma Triglyceride ◽  
Whole Body ◽  
Elevated Plasma ◽  
High Fat ◽  
Deficient Mice

ABSTRACTElevated plasma triglyceride levels are associated with metabolic disease. Angiopoietin-like protein 4 (ANGPTL4) regulates plasma triglyceride levels by inhibiting lipoprotein lipase (LPL). Our aim was to investigate the role of tissue-specific ANGPTL4 expression in the setting of high fat diet. Adipocyte- and hepatocyte-specific ANGPTL4 deficient mice were fed a high fat diet (60% kCal from fat) for either 12 weeks or 6 months. We performed plasma metabolic measurements, triglyceride clearance and uptake assays, LPL activity assays, and assessed glucose homeostasis. Mice lacking adipocyte ANGPTL4 recapitulated the triglyceride phenotypes of whole-body ANGPTL4 deficiency, whereas mice lacking hepatocyte ANGPTL4 had few triglyceride phenotypes. When fed a high fat diet (HFD), mice deficient in adipocyte ANGPTL4 gained more weight, had enhanced adipose LPL activity, and initially had improved glucose and insulin sensitivity. However, this improvement was largely lost after 6 months on HFD. Conversely, mice deficient in hepatocyte ANGPTL4 initially displayed no differences in glucose homeostasis, but began to manifest improved glucose tolerance after 6 months on HFD. We conclude that it is primarily adipocyte-derived ANGPTL4 that is responsible for regulating plasma triglyceride levels. Deficiency in adipocyte- or hepatocyte-derived ANGPTL4 may confer some protections against high fat diet induced dysregulation of glucose homeostasis.

scholarly journals Estradiol regulates daily rhythms underlying diet-induced obesity in female mice

2019 ◽  
Vol 317 (6) ◽  
pp. E1172-E1181 ◽  
Author(s):  
Oluwabukola Omotola ◽  
Sandra Legan ◽  
Emily Slade ◽  
Ayooluwatomiwa Adekunle ◽  
Julie S. Pendergast
Keyword(s):  
Circadian Rhythms ◽  
Eating Behavior ◽  
High Fat Diet ◽  
Circadian System ◽  
High Fat ◽  
Daily Rhythms ◽  
Diet Induced Obesity ◽  
Ovariectomized Mice ◽  
Circulating Levels

The circadian system is a critical regulator of metabolism and obesity in males, but its role in regulating obesity in females is poorly understood. Because there are sex differences in the development of obesity and susceptibility to obesity-related disorders, we sought to determine the role of estrogens in regulating the circadian mechanisms underlying diet-induced obesity. When fed high-fat diet, C57BL/6J male mice gain weight, whereas females are resistant to diet-induced obesity. Here, we demonstrate that estradiol regulates circadian rhythms in females to confer resistance to diet-induced obesity. We found that ovariectomized females with undetectable circulating estrogens became obese and had disrupted daily rhythms of eating behavior and locomotor activity when fed a high-fat diet. The phase of the liver molecular circadian rhythm was also altered by high-fat diet feeding in ovariectomized mice. Estradiol replacement in ovariectomized females a fed high-fat diet rescued these behavioral and tissue rhythms. Additionally, restoring the daily rhythm of eating behavior in ovariectomized females with time-restricted feeding inhibited diet-induced obesity and insulin resistance. Together, these data suggest that the circadian system is a target for treating obesity and its comorbidities in women after menopause, when circulating levels of estrogens are too low to protect their circadian rhythms.

scholarly journals The Motor Neuron-Like Cell Line NSC-34 and Its Parent Cell Line N18TG2 Have Glycogen that is Degraded Under Cellular Stress

2021 ◽  
Author(s):  
Brigitte Pfeiffer-Guglielmi ◽  
Ralf-Peter Jansen
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Glycogen Phosphorylase ◽  
Metabolic Stress ◽  
Neuronal Cell ◽  
Parent Cell ◽  
Normal Brain ◽  
Storage Site ◽  
Neuronal Cell Lines

AbstractBrain glycogen has a long and versatile history: Primarily regarded as an evolutionary remnant, it was then thought of as an unspecific emergency fuel store. A dynamic role for glycogen in normal brain function has been proposed later but exclusively attributed to astrocytes, its main storage site. Neuronal glycogen had long been neglected, but came into focus when sensitive technical methods allowed quantification of glycogen at low concentration range and the detection of glycogen metabolizing enzymes in cells and cell lysates. Recently, an active role of neuronal glycogen and even its contribution to neuronal survival could be demonstrated. We used the neuronal cell lines NSC-34 and N18TG2 and could demonstrate that they express the key-enzymes of glycogen metabolism, glycogen phosphorylase and glycogen synthase and contain glycogen which is mobilized on glucose deprivation and elevated potassium concentrations, but not by hormones stimulating cAMP formation. Conditions of metabolic stress, namely hypoxia, oxidative stress and pH lowering, induce glycogen degradation. Our studies revealed that glycogen can contribute to the energy supply of neuronal cell lines in situations of metabolic stress. These findings shed new light on the so far neglected role of neuronal glycogen. The key-enzyme in glycogen degradation is glycogen phosphorylase. Neurons express only the brain isoform of the enzyme that is supposed to be activated primarily by the allosteric activator AMP and less by covalent phosphorylation via the cAMP cascade. Our results indicate that neuronal glycogen is not degraded upon hormone action but by factors lowering the energy charge of the cells directly.

scholarly journals Female Mice with Selenocysteine tRNA Deletion in Agrp Neurons Maintain Leptin Sensitivity and Resist Weight Gain While on a High-Fat Diet

2021 ◽  
Vol 22 (20) ◽  
pp. 11010
Author(s):  
Daniel J. Torres ◽  
Matthew W. Pitts ◽  
Lucia A. Seale ◽  
Ann C. Hashimoto ◽  
Katlyn J. An ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Energy Homeostasis ◽  
Redox Balance ◽  
Conditional Knockout ◽  
Sexually Dimorphic ◽  
High Fat ◽  
Leptin Sensitivity ◽  
To Come ◽  
Insight Into

The role of the essential trace element selenium in hypothalamic physiology has begun to come to light over recent years. Selenium is used to synthesize a family of proteins participating in redox reactions called selenoproteins, which contain a selenocysteine residue in place of a cysteine. Past studies have shown that disrupted selenoprotein expression in the hypothalamus can adversely impact energy homeostasis. There is also evidence that selenium supports leptin signaling in the hypothalamus by maintaining proper redox balance. In this study, we generated mice with conditional knockout of the selenocysteine tRNA[Ser]Sec gene (Trsp) in an orexigenic cell population called agouti-related peptide (Agrp)-positive neurons. We found that female TrspAgrpKO mice gain less weight while on a high-fat diet, which occurs due to changes in adipose tissue activity. Female TrspAgrpKO mice also retained hypothalamic sensitivity to leptin administration. Male mice were unaffected, however, highlighting the sexually dimorphic influence of selenium on neurobiology and energy homeostasis. These findings provide novel insight into the role of selenoproteins within a small yet heavily influential population of hypothalamic neurons.

scholarly journals Role of astroglia in diet-induced central neuroplasticity

2019 ◽  
Vol 121 (4) ◽  
pp. 1195-1206 ◽  
Author(s):  
Courtney Clyburn ◽  
Kirsteen N. Browning
Keyword(s):  
Systemic Inflammation ◽  
High Fat Diet ◽  
Type Ii Diabetes ◽  
Energy Homeostasis ◽  
High Fat ◽  
Health Crisis ◽  
Diet Induced Obesity ◽  
Reward Pathways ◽  
Astroglial Activation

Obesity, characterized by increased adiposity that develops when energy intake outweighs expenditure, is rapidly becoming a serious health crisis that affects millions of people worldwide and is associated with severe comorbid disorders including hypertension, cardiovascular disease, and type II diabetes. Obesity is also associated with the dysregulation of central neurocircuits involved in the control of autonomic, metabolic, and cognitive functions. Systemic inflammation associated with diet-induced obesity (DIO) has been proposed to be responsible for the development of these comorbidities as well as the dysregulation of central neurocircuits. A growing body of evidence suggests, however, that exposure to a high-fat diet (HFD) may cause neuroinflammation and astroglial activation even before systemic inflammation develops, which may be sufficient to cause dysregulation of central neurocircuits involved in energy homeostasis before the development of obesity. The purpose of this review is to summarize the current literature exploring astroglial-dependent modulation of central circuits following exposure to HFD and DIO, including not only dysregulation of neurocircuits involved in energy homeostasis and feeding behavior, but also the dysregulation of learning, memory, mood, and reward pathways.

scholarly journals Regulation of plasma triglyceride partitioning by adipose-derived ANGPTL4 in mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kathryn M. Spitler ◽  
Shwetha K. Shetty ◽  
Emily M. Cushing ◽  
Kelli L. Sylvers-Davie ◽  
Brandon S. J. Davies
Keyword(s):  
Glucose Homeostasis ◽  
High Fat Diet ◽  
Normal Diet ◽  
Plasma Triglyceride ◽  
Whole Body ◽  
Activity Levels ◽  
High Fat ◽  
Important Regulator ◽  
Fat Feeding

AbstractElevated plasma triglyceride levels are associated with metabolic disease. Angiopoietin-like protein 4 (ANGPTL4) regulates plasma triglyceride levels by inhibiting lipoprotein lipase (LPL). Our aim was to investigate the role of adipocyte-specific deficiency of ANGPTL4 in mice during high fat diet feeding. Adipocyte-specific ANGPTL4 deficient mice were fed a high fat diet (60% kCal from fat) for either 12 weeks or 6 months. We performed plasma metabolic measurements, triglyceride clearance and uptake assays, LPL activity assays, and assessed glucose homeostasis. Mice lacking adipocyte ANGPTL4 recapitulated the triglyceride phenotypes of whole-body ANGPTL4 deficiency, including increased adipose LPL activity, lower plasma triglyceride levels, and increased uptake of triglycerides into adipose tissue. When fed a high fat diet (HFD), these mice continued to display enhanced adipose LPL activity and initially had improved glucose and insulin sensitivity. However, after 6 months on HFD, the improvements in glucose homeostasis were largely lost. Moreover, despite higher adipose LPL activity levels, mice lacking adipocyte ANGPTL4 no longer had increased triglyceride uptake into adipose compared to littermate controls after chronic high-fat feeding. These observations suggest that after chronic high-fat feeding LPL is no longer rate-limiting for triglyceride delivery to adipocytes. We conclude that while adipocyte-derived ANGPTL4 is an important regulator of plasma triglyceride levels and triglyceride partitioning under normal diet conditions, its role is diminished after chronic high-fat feeding.

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