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Short-term overfeeding increases the in vivo activity of CPT1 in the arcuate. (A) CPT1-specific activity in the arcuate nucleus (ARC), periventricular nucleus (PVN), and lateral hypothalamic area (LHA) of SC and OF rats. CPT1A and CPT1B mRNA measured in the arcuate nucleus, periventricular nucleus, and lateral hypothalamic area of SC and OF rats. (B) Western blot analysis of MBH-phosphorylated ACC (pACC) and total ACC. Band intensity of pACC was normalized to that of β-tubulin. Results are expressed as average of 4 different Western blots. (C) MBH malonyl-CoA levels in SC and OF rats expressed as pmol/mg wet wt and as pmol/mg protein. *P < 0.05 versus SC.
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Short-term overfeeding blunts the central effects of fatty acids on food intake and glucose production. This acquired defect in nutrient sensing could contribute to the rapid onset of hyperphagia and insulin resistance in this model. Here we examined whether central inhibition of lipid oxidation is sufficient to restore the hypothalamic levels of l...
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... possible explanation for the muted effect of increased lipid availability on the MBH accumulation of LCFA-CoAs is that the cellular metabolism of esterified LCFA is accelerated in OF com- pared with SC rats. Indeed the activity of acyl-CoA hydrolase was modestly higher (Supplemental Figure 1A), and CPT1 activity was significantly (~42%) and selectively increased, in the MBH (arcu- ate nuclei) of OF rats (Figure 2A). Hypothalamic nuclei express 2 isoforms of CPT1, the muscle isoform encoded by the CPT1B gene and the liver isoform encoded by the CPT1A gene. ...
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... nuclei express 2 isoforms of CPT1, the muscle isoform encoded by the CPT1B gene and the liver isoform encoded by the CPT1A gene. The latter is the prevalent isoform in the arcuate (Figure 2A). Short-term over- feeding did not increase the expression of either CPT1 transcript in the arcuate, suggesting that the increased enzymatic activity is likely due to increased protein stability rather than to increased gene expression (Figure 2A). ...
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... latter is the prevalent isoform in the arcuate (Figure 2A). Short-term over- feeding did not increase the expression of either CPT1 transcript in the arcuate, suggesting that the increased enzymatic activity is likely due to increased protein stability rather than to increased gene expression (Figure 2A). The cellular level of malonyl-CoA, a potent endogenous inhibitor of CPT1, largely determines the in vivo activity of CPT1A. ...
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... carboxylase (ACC) catalyzes the forma- tion of malonyl-CoA from acetyl-CoA ( Figure 1A), and its activity is decreased by phosphorylation. ACC phosphorylation (pACC) was markedly increased in the MBH of OF compared with that of SC rats ( Figure 2B). Consistent with this finding, the MBH lev- els of malonyl-CoA were approximately 70% lower in OF than in Short-term overfeeding impairs hypo- thalamic lipid sensing. ...
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... rats ( Figure 2C). On the other hand, we could not detect sig- nificant changes in the MBH expression of AMP-activated protein kinase (AMPK) and fatty acid synthase nor in the phosphorylation of AMPK (Supplemental Figure 2A). ...
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... rats ( Figure 2C). On the other hand, we could not detect sig- nificant changes in the MBH expression of AMP-activated protein kinase (AMPK) and fatty acid synthase nor in the phosphorylation of AMPK (Supplemental Figure 2A). Taken together, these obser- vations raise the possibility that decreasing oxidative metabolism of LCFAs within the MBH could restore hypothalamic lipid sens- ing and curtail feeding behavior in OF rats ( Figure 1A). ...
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... decreases the phos- phorylation and activity of AMPK in the arcuate, and this effect appears to be required for its anorexigenic effect (14). Short-term overfeeding failed to alter the expression and phosphorylation of AMPK in the MBH (Supplemental Figure 2A). SOCS3 is a potent inhibitor of leptin signaling and is emerging as an important determinant of leptin resistance in models of chronic obesity (23). ...
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... is a potent inhibitor of leptin signaling and is emerging as an important determinant of leptin resistance in models of chronic obesity (23). However, we did not observe an increase in SOCS3 expres- sion in the MBH of OF rats (Supplemental Figure 2B). To gain insight into potential mechanisms responsible for the changes described above in the feeding behavior in OF rats, we next ana- lyzed the effect of overfeeding and central CPT1A inhibition on the gene expression of the orexigenic neuropeptides neuropep- tide Y (NPY) and agouti-related peptide (AGRP). ...
Citations
... Moreover, the hyperinsulinemia induced by such VMH norepinephrine activity was found to feedback centrally to maintain such stimulated norepinephrine release at the VMH [143], closing/perpetuating a cardiometabolic syndrome precipitating loop, independent of feeding. Of additional note, the VMH is a prominent CNS fuel sensing center, wherein increases in local VMH levels of FFA or glucose (similar to post-meal levels) induce a VMH response that facilitates peripheral glucose uptake [144][145][146][147]. Norepinephrine administration to the VMH was found to block this VMH response to FFA and glucose, thereby facilitating glucose intolerance and, importantly, such administration also simultaneously elevated blood pressure [148][149][150][151]. ...
Despite enormous global efforts within clinical research and medical practice to reduce cardiovascular disease(s) (CVD), it still remains the leading cause of death worldwide. While genetic factors clearly contribute to CVD etiology, the preponderance of epidemiological data indicate that a major common denominator among diverse ethnic populations from around the world contributing to CVD is the composite of Western lifestyle cofactors, particularly Western diets (high saturated fat/simple sugar [particularly high fructose and sucrose and to a lesser extent glucose] diets), psychosocial stress, depression, and altered sleep/wake architecture. Such Western lifestyle cofactors are potent drivers for the increased risk of metabolic syndrome and its attendant downstream CVD. The central nervous system (CNS) evolved to respond to and anticipate changes in the external (and internal) environment to adapt survival mechanisms to perceived stresses (challenges to normal biological function), including the aforementioned Western lifestyle cofactors. Within the CNS of vertebrates in the wild, the biological clock circuitry surveils the environment and has evolved mechanisms for the induction of the obese, insulin-resistant state as a survival mechanism against an anticipated ensuing season of low/no food availability. The peripheral tissues utilize fat as an energy source under muscle insulin resistance, while increased hepatic insulin resistance more readily supplies glucose to the brain. This neural clock function also orchestrates the reversal of the obese, insulin-resistant condition when the low food availability season ends. The circadian neural network that produces these seasonal shifts in metabolism is also responsive to Western lifestyle stressors that drive the CNS clock into survival mode. A major component of this natural or Western lifestyle stressor-induced CNS clock neurophysiological shift potentiating the obese, insulin-resistant state is a diminution of the circadian peak of dopaminergic input activity to the pacemaker clock center, suprachiasmatic nucleus. Pharmacologically preventing this loss of circadian peak dopaminergic activity both prevents and reverses existing metabolic syndrome in a wide variety of animal models of the disorder, including high fat-fed animals. Clinically, across a variety of different study designs, circadian-timed bromocriptine-QR (quick release) (a unique formulation of micronized bromocriptine—a dopamine D2 receptor agonist) therapy of type 2 diabetes subjects improved hyperglycemia, hyperlipidemia, hypertension, immune sterile inflammation, and/or adverse cardiovascular event rate. The present review details the seminal circadian science investigations delineating important roles for CNS circadian peak dopaminergic activity in the regulation of peripheral fuel metabolism and cardiovascular biology and also summarizes the clinical study findings of bromocriptine-QR therapy on cardiometabolic outcomes in type 2 diabetes subjects.
... It uses simple C language as a programming language based on open and free original coding. Arduino IDE was added later as a software environment for computer-related programs [6]. The Arduino controller is shown in Figure 5. ...
Arduino platform is a new hardware and software combination platform that is widely used, flexible, easy to operate, and rapidly developing. In this paper, the design and implementation of the DC chopper circuit were conducted based on the Arduino platform. Firstly, the power signal and trigger signal are output in the form of programming on the Arduino platform, and the rest of the circuit is built on the breadboard in the form of hardware. Finally, the design waveform is obtained. This paper introduces the basic working principles of four power conversion circuits, conducts circuit simulation on MATLAB software and obtains the ideal output waveform, and uses C language programming to trigger control signal generation, generates corresponding electrical signals through compilation and USB wire transmission to Arduino controller, and builds relevant circuits. This paper makes use of the advantages of the breadboard, fully combines the theoretical knowledge and circuit connection, and finally observes the output waveform through an oscilloscope, and compares the waveform of the actual circuit with the simulation results of MATLAB.
... In particular, inhibition of CPT1A activity in the MBH by icv injection of a specific riboprobe results in food intake suppression, downregulation of hypothalamic orexigenic neuropeptides (AgRP and NPY), and reduced hepatic gluconeogenesis. 67,68 This satiation activity is accompanied by an increase in long-chain FAs in the hypothalamus, and, in fact, inhibition of hypothalamic CPT1A activity itself has been shown to reproduce the effects of icv injection with oleic acid on food intake and glucose production. 11 It is therefore likely that long-chain FA accumulation rather than FA influx into the mitochondria is a major component in hypothalamic lipid sensing and satiety signaling. ...
Tackling the growing incidence and prevalence of obesity urgently requires uncovering new molecular pathways with therapeutic potential. The brain, and in particular the hypothalamus, is a major integrator of metabolic signals from peripheral tissues that regulate functions such as feeding behavior and energy expenditure. In obesity, hypothalamic capacity to sense nutritional status and regulate these functions is altered. An emerging line of research is that hypothalamic lipid metabolism plays a critical role in regulating energy balance. Here we focus on the carnitine palmitoyltransferase 1 (CPT1) enzyme family responsible for long‐chain fatty acid metabolism. The evidence suggests that two of its isoforms expressed in the brain, CPT1A and CPT1C, play a crucial role in hypothalamic lipid metabolism, and their promise as targets in food intake and body weight management is currently being intensively investigated. In this review we describe and discuss the metabolic actions and potential upstream and downstream effectors of hypothalamic CPT1 isoforms, and posit the need to develop innovative nanomedicine platforms for selective targeting of CPT1 and related nutrient sensors in specific brain areas as potential next‐generation therapy to treat obesity. This article is protected by copyright. All rights reserved.
... Early studies have shown that rodents subjected to three days of feeding with a diet enriched in animal fat (high-fat diet) induced insulin resistance affecting mainly the liver. Interestingly, it was later shown that, under these conditions, the hypothalamic glucoregulatory response to fatty acids was markedly reduced [19,38,39]. These studies clearly indicated that an acquired defect that interfered with brain nutrient sensing was induced by the consumption of a diet enriched in saturated fat. ...
... However, what is the mechanism(s) underlying this form of acquired "metabolic disability" that renders the organism unable to respond normally to nutrient cues? The answer to this question is largely unknown; however, studies in rats [39] have led to two relevant findings: (1) HFD feeding caused a marked decrease in the levels of hypothalamic longchain fatty acyl CoAs (LCFA-CoA); and (2) restoration of the hypothalamic LCFA-CoA pool normalized nutrient-dependent glucose regulation. These metabolic deficits were in line with our previous studies that indicated the central metabolism of nutrients in the hypothalamus required an increase in the local levels of oleoyl-CoA [22]. ...
... Furthermore, we postulate that restoring the levels of key hypothalamic molecules implicated in the sensing mechanism(s) such as malonyl-CoA or oleyl-CoA would be an important avenue of research. In fact, studies in rodents have suggested that restoring the levels of long-chain fatty acyl-CoAs in the hypothalamus could be helpful to overcome the metabolic dysfunctions brought about by high-fat diets [39]. A nutraceutical candidate to achieve this restoration is leucine itself, since it is a ketogenic amino acid that improves insulin action [22]; we postulate that leucine could be a dietary supplement to overcome the damaging effects of chronic HFD feeding. ...
A sedentary lifestyle and excessive nutrient intake resulting from the consumption of high-fat and calorie-rich diets are environmental factors contributing to the rapid growth of the current pandemic of type 2 diabetes mellitus (DM2). Fasting hyperglycemia, an established hallmark of DM2, is caused by excessive production of glucose by the liver, resulting in the inability of insulin to suppress endogenous glucose production. To prevent inappropriate elevations of circulating glucose resulting from changes in nutrient availability, mammals rely on complex mechanisms for continuously detecting these changes and to respond to them with metabolic adaptations designed to modulate glucose output. The mediobasal hypothalamus (MBH) is the key center where nutritional cues are detected and appropriate modulatory responses are integrated. However, certain environmental factors may have a negative impact on these adaptive responses. For example, consumption of a diet enriched in saturated fat in rodents resulted in the development of a metabolic defect that attenuated these nutrient sensing mechanisms, rendering the animals prone to developing hyperglycemia. Thus, high-fat feeding leads to a state of “metabolic disability” in which animals’ glucoregulatory responses fail. We postulate that the chronic faltering of the hypothalamic glucoregulatory mechanisms contributes to the development of metabolic disease.
... In the hypothalamus and in astrocytes, glucose, via AMPK, can inhibit oxidation and esterification of certain long-chain fatty acids [464]. This evidence may be relevant for a therapy against diabetes, as inhibition of lipid oxidation is sufficient to restore glucose and energy homeostasis in overfed rats [465]. In the presence of lipopolysaccharide, activation of AMPK maintains blood brain barrier integrity by reducing ROS [466]. ...
Sirtuins are a family of highly conserved NAD+-dependent proteins and this dependency links Sirtuins directly to metabolism. Sirtuins’ activity has been shown to extend the lifespan of several organisms and mainly through the post-translational modification of their many target proteins, with deacetylation being the most common modification. The seven mammalian Sirtuins, SIRT1 through SIRT7, have been implicated in regulating physiological responses to metabolism and stress by acting as nutrient sensors, linking environmental and nutrient signals to mammalian metabolic homeostasis. Furthermore, mammalian Sirtuins have been implicated in playing major roles in mammalian pathophysiological conditions such as inflammation, obesity and cancer. Mammalian Sirtuins are expressed heterogeneously among different organs and tissues, and the same holds true for their substrates. Thus, the function of mammalian Sirtuins together with their substrates is expected to vary among tissues. Any therapy depending on Sirtuins could therefore have different local as well as systemic effects. Here, an introduction to processes relevant for the actions of Sirtuins, such as metabolism and cell cycle, will be followed by reasoning on the system-level function of Sirtuins and their substrates in different mammalian tissues. Their involvement in the healthy metabolism and metabolic disorders will be reviewed and critically discussed.
... The hypothalamus detects amino acids (Arrieta-Cruz et al., 2013;Su et al., 2012), oleic acids (Obici et al., 2002b;Pocai et al., 2006), and glucose (Lam et al., 2005a) to regulate hepatic glucose production. Hypothalamic K ATP channels is required for glucose sensing (Lam et al., 2005a), and such a finding was recently replicated in rodents as well as implicated in humans (Carey et al., 2020). ...
Hypothalamic regulation of lipid and glucose homeostasis is emerging, but whether the dorsal vagal complex (DVC) senses nutrients and regulates hepatic nutrient metabolism remain unclear. Here, we found in rats DVC oleic acid infusion suppressed hepatic secretion of VLDL-TG, which was disrupted by inhibiting DVC long-chain fatty acyl-CoA synthetase that in parallel disturbed lipid homeostasis during intravenous lipid infusion. DVC glucose infusion elevated local glucose levels similarly as intravenous glucose infusion and suppressed hepatic glucose production. This was independent of lactate metabolism as inhibiting lactate-dehydrogenase failed to disrupt glucose sensing and neither could DVC lactate infusion recapitulated glucose effect. DVC oleic acid and glucose infusion failed to lower VLDL-TG secretion and glucose production in high-fat fed rats, while inhibiting DVC farnesoid X receptor enhanced oleic acid but not glucose sensing. Thus, an impairment of DVC nutrient sensing may lead to the disruption of lipid and glucose homeostasis in metabolic syndrome.
... But, what about the cellular target of malonyl-CoA and how is its signal transmitted? The group of Rossetti pointed CPT1A as a downstream target of malonyl-CoA, since inhibition of CPT1A in the hypothalamus of rodents resulted in diminished food intake and hepatic glucose production, and body weight attenuation [52][53][54] (Fig 3). In line with this evidence, CPT1A overexpression in the VMH of rats increased food intake and body weight [55,56]. ...
Nutrients, hormones and the energy sensor AMP-activated protein kinase (AMPK) tightly regulate the intracellular levels of the metabolic intermediary malonyl-CoA, which is a precursor of fatty acid synthesis and a negative regulator of fatty acid oxidation. In the brain, the involvement of malonyl-CoA in the control of food intake and energy homeostasis has been known for decades. However, recent data uncover a new role in cognition and brain development. The sensing of malonyl-CoA by carnitine palmitoyltransferase 1 (CPT1) proteins regulates a variety of functions, such as the fate of neuronal stem cell precursors, the motility of lysosomes in developing axons, the trafficking of glutamate receptors to the neuron surface (necessary for proper synaptic function) and the metabolic coupling between astrocytes and neurons. We discuss the relevance of those recent findings evidencing how nutrients and metabolic disorders impact cognition. We also enumerate all nutritional and hormonal conditions that are known to regulate malonyl-CoA levels in the brain, reflect on protein malonylation as a new post-translational modification, and give a reasoned vision of the opportunities and challenges that future research in the field could address.
... Fasting reduces the production of hypothalamic malonyl-CoA [152], shifting metabolic substrate utilization away from glycolysis and toward lipid oxidation [153]. Malonyl-CoA acts indirectly on CPT1 and thus prevents the access of long-chain fatty acyl-CoA to the mitochondria, which would decrease food intake [154,155]. Hypothalamic fatty acid metabolism mediates the orexigenic effect of ghrelin [156,157]. Ghrelin-induced food intake activates hypothalamic sirtuin 1 (SIRT-1), which deacetylates p53 and thereby activates AMPK [158]. ...
Ghrelin is a relatively novel multifaceted hormone that has been found to exert a plethora of physiological effects. In this review, we found/confirmed that ghrelin has effect on all body systems. It induces appetite; promotes the use of carbohydrates as a source of fuel while sparing fat; inhibits lipid oxidation and promotes lipogenesis; stimulates the gastric acid secretion and motility; improves cardiac performance; decreases blood pressure; and protects the kidneys, heart, and brain. Ghrelin is important for learning, memory, cognition, reward, sleep, taste sensation, olfaction, and sniffing. It has sympatholytic, analgesic, antimicrobial, antifibrotic, and osteogenic effects. Moreover, ghrelin makes the skeletal muscle more excitable and stimulates its regeneration following injury; delays puberty; promotes fetal lung development; decreases thyroid hormone and testosterone; stimulates release of growth hormone, prolactin, glucagon, adrenocorticotropic hormone, cortisol, vasopressin, and oxytocin; inhibits insulin release; and promotes wound healing. Ghrelin protects the body by different mechanisms including inhibition of unwanted inflammation and induction of autophagy. Having a clear understanding of the ghrelin effect in each system has therapeutic
implications. Future studies are necessary to elucidate the molecular mechanisms of ghrelin actions as well as its application as a GHSR agonist to treat most common diseases in each system without any paradoxical outcomes on the other systems.
... Fasting reduces the production of hypothalamic malonyl-CoA [152], shifting metabolic substrate utilization away from glycolysis and toward lipid oxidation [153]. Malonyl-CoA acts indirectly on CPT1 and thus prevents the access of long-chain fatty acyl-CoA to the mitochondria, which would decrease food intake [154,155]. Hypothalamic fatty acid metabolism mediates the orexigenic effect of ghrelin [156,157]. Ghrelin-induced food intake activates hypothalamic sirtuin 1 (SIRT-1), which deacetylates p53 and thereby activates AMPK [158]. ...
Ghrelin is a relatively novel multifaceted hormone that has been found to exert a plethora of physiological effects. In this review, we found/confirmed that ghrelin has effect on all body systems. It induces appetite; promotes the use of carbohydrates as a source of fuel while sparing fat; inhibits lipid oxidation and promotes lipogenesis; stimulates the gastric acid secretion and motility; improves cardiac performance; decreases blood pressure; and protects the kidneys, heart, and brain. Ghrelin is important for learning, memory, cognition, reward, sleep, taste sensation, olfaction, and sniffing. It has sympatholytic, analgesic, antimicrobial, antifibrotic, and osteogenic effects. Moreover, ghrelin makes the skeletal muscle more excitable and stimulates its regeneration following injury; delays puberty; promotes fetal lung development; decreases thyroid hormone and testosterone; stimulates release of growth hormone, prolactin, glucagon, adrenocorticotropic hormone, cortisol, vasopressin, and oxytocin; inhibits insulin release; and promotes wound healing. Ghrelin protects the body by different mechanisms including inhibition of unwanted inflammation and induction of autophagy. Having a clear understanding of the ghrelin effect in each system has therapeutic implications. Future studies are necessary to elucidate the molecular mechanisms of ghrelin actions as well as its application as a GHSR agonist to treat most common diseases in each system without any paradoxical outcomes on the other systems.
... This is consistent with the observation that brain glucose uptake is decreased in people with type 1 diabetes [53] as discussed above, and suggests that leptin enhances (or restores) hypothalamic glucose metabolism to lactate and lowers glucose production in hyperglycemic conditions ( Figure 2). In fact, hypothalamic leptin administration enhances glucose infusion to increase hypothalamic malonyl-CoA levels in mice [21], a downstream mediator of the hypothalamic AMPK-malonyl-CoA-CPT1 axis that is sufficient and necessary for glucose sensing to lower glucose production in rats as discussed above [27,114] ( Figure 2). These studies collectively imply that during glucose excess conditions, leptin enhances hypothalamic glucose sensing mechanisms to lower glucose production and maintain whole-body glucose homeostasis in insulin-deficient conditions ( Figure 2). ...
Background
In response to energy abundant or deprived conditions, nutrients and hormones activate hypothalamic pathways to maintain energy and glucose homeostasis. The underlying CNS mechanisms, however, remain elusive in rodents and humans.
Scope of Review
Here, we first discuss brain glucose sensing mechanisms in the presence of a rise or fall of plasma glucose levels, and highlight defects in hypothalamic glucose sensing disrupts in vivo glucose homeostasis in high-fat fed, obese, and/or diabetic conditions. Second, we discuss brain leptin signalling pathways that impact glucose homeostasis in glucose-deprived and excessed conditions, and propose that leptin enhances hypothalamic glucose sensing and restores glucose homeostasis in short-term high-fat and/or uncontrolled diabetic conditions.
Major Conclusions
In conclusion, we believe basic studies that investigate the interaction of glucose sensing and leptin action in the brain will address the translational impact of hypothalamic glucose sensing in diabetes and obesity.
