Fatty acid-induced astrocyte ketone production and the control of food intake

Obesity and Type 2 diabetes are major worldwide public health issues today. A relationship between total fat intake and obesity has been found. In addition, the mechanisms of long-term and excessive high-fat diet (HFD) intake in the development of obesity still need to be elucidated. The ventromedial hypothalamus (VMH) is a major site involved in the regulation of glucose and energy homeostasis where “metabolic sensing neurons” integrate metabolic signals from the periphery. Among these signals, fatty acids (FA) modulate the activity of VMH neurons using the FA translocator/CD36, which plays a critical role in the regulation of energy and glucose homeostasis. During low-fat diet (LFD) intake, FA are oxidized by VMH astrocytes to fuel their ongoing metabolic needs. However, HFD intake causes VMH astrocytes to use FA to generate ketone bodies. We postulate that these astrocyte-derived ketone bodies are exported to neurons where they produce excess ATP and reactive oxygen species, which override CD36-mediated FA sensing and act as a signal to decrease short-term food intake. On a HFD, VMH astrocyte-produced ketones reduce elevated caloric intake to LFD levels after 3 days in rats genetically predisposed to resist (DR) diet-induced obesity (DIO), but not leptin-resistant DIO rats. This suggests that, while VMH ketone production on a HFD can contribute to protection from obesity, the inherent leptin resistance overrides this inhibitory action of ketone bodies on food intake. Thus, astrocytes and neurons form a tight metabolic unit that is able to monitor circulating nutrients to alter food intake and energy homeostasis.

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Role of VMH ketone bodies in adjusting caloric intake to increased dietary fat content in DIO and DR rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00015.2015 ◽

2015 ◽

Vol 308 (10) ◽

pp. R872-R878 ◽

Cited By ~ 17

Author(s):

Christelle Le Foll ◽

Ambrose A. Dunn-Meynell ◽

Henry M. Miziorko ◽

Barry E. Levin

Keyword(s):

Food Intake ◽

Potential Role ◽

Ketone Bodies ◽

Caloric Intake ◽

High Energy ◽

Leptin Resistance ◽

Hypothalamic Nucleus ◽

Diet Intake ◽

Body Production

The objective of this study was to determine the potential role of astrocyte-derived ketone bodies in regulating the early changes in caloric intake of diet induced-obese (DIO) versus diet-resistant (DR) rats fed a 31.5% fat high-energy (HE) diet. After 3 days on chow or HE diet, DR and DIO rats were assessed for their ventromedial hypothalamic (VMH) ketone bodies levels and neuronal ventromedial hypothalamic nucleus (VMN) sensing using microdialysis coupled to continuous food intake monitoring and calcium imaging in dissociated neurons, respectively. DIO rats ate more than DR rats over 3 days of HE diet intake. On day 3 of HE diet intake, DR rats reduced their caloric intake while DIO rats remained hyperphagic. Local VMH astrocyte ketone bodies production was similar between DR and DIO rats during the first 6 h after dark onset feeding but inhibiting VMH ketone body production in DR rats on day 3 transiently returned their intake of HE diet to the level of DIO rats consuming HE diet. In addition, dissociated VMN neurons from DIO and DR rats were equally sensitive to the largely excitatory effects of β-hydroxybutyrate. Thus while DR rats respond to increased VMH ketone levels by decreasing their intake after 3 days of HE diet, this is not the case of DIO rats. These data suggest that DIO inherent leptin resistance prevents ketone bodies inhibitory action on food intake.

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Chronic Gqsignaling in AgRP neurons does not cause obesity

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2004941117 ◽

2020 ◽

Vol 117 (34) ◽

pp. 20874-20880 ◽

Cited By ~ 1

Author(s):

Sedona N. Ewbank ◽

Carlos A. Campos ◽

Jane Y. Chen ◽

Anna J. Bowen ◽

Stephanie L. Padilla ◽

...

Keyword(s):

Body Weight ◽

Food Intake ◽

Energy Expenditure ◽

Energy Homeostasis ◽

Caloric Intake ◽

Metabolic Effects ◽

Leptin Resistance ◽

Published Data ◽

Fat Consumption ◽

Baseline Levels

Maintaining energy homeostasis requires coordinating physiology and behavior both on an acute timescale to adapt to rapid fluctuations in caloric intake and on a chronic timescale to regulate body composition. Hypothalamic agouti-related peptide (AgRP)-expressing neurons are acutely activated by caloric need, and this acute activation promotes increased food intake and decreased energy expenditure. On a longer timescale, AgRP neurons exhibit chronic hyperactivity under conditions of obesity and high dietary fat consumption, likely due to leptin resistance; however, the behavioral and metabolic effects of chronic AgRP neuronal hyperactivity remain unexplored. Here, we use chemogenetics to manipulate Gqsignaling in AgRP neurons in mice to explore the hypothesis that chronic activation of AgRP neurons promotes obesity. Inducing chronic Gqsignaling in AgRP neurons initially increased food intake and caused dramatic weight gain, in agreement with published data; however, food intake returned to baseline levels within 1 wk, and body weight returned to baseline levels within 60 d. Additionally, we found that, when mice had elevated body weight due to chronic Gqsignaling in AgRP neurons, energy expenditure was not altered but adiposity and lipid metabolism were both increased, even under caloric restriction. These findings reveal that the metabolic and behavioral effects of chronic Gqsignaling in AgRP neurons are distinct from the previously reported effects of acute Gqsignaling and also of leptin insensitivity.

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Region-Specific Reduction in Leptin-Induced Phosphorylation of Signal Transducer and Activator of Transcription-3 (STAT3) in the Rat Hypothalamus Is Associated with Leptin Resistance during Pregnancy

Endocrinology ◽

10.1210/en.2004-0338 ◽

2004 ◽

Vol 145 (8) ◽

pp. 3704-3711 ◽

Cited By ~ 98

Author(s):

S. R. Ladyman ◽

D. R. Grattan

Keyword(s):

Food Intake ◽

Arcuate Nucleus ◽

Ventromedial Hypothalamus ◽

Leptin Resistance ◽

Signal Transducer ◽

Pregnant Rats ◽

Hypothalamic Nuclei ◽

Stat3 Phosphorylation ◽

Vehicle Treatment ◽

Plasma Leptin

Abstract Leptin concentrations increase during pregnancy, but this does not prevent the pregnancy-induced increase in food intake, suggesting a state of leptin resistance. This study investigated the response to intracerebroventricular leptin administration in pregnant rats. After fasting, nonpregnant, d-7 and d-14 pregnant rats received leptin (4 μg) or vehicle, then food intake was measured. Serial blood samples were collected in another group of rats to determine plasma leptin concentrations. Further groups of d-14 pregnant and nonpregnant rats were killed after leptin or vehicle treatment, and brains were collected. Hypothalamic nuclei were microdissected, and levels of signal transducer and activator of transcription (STAT)3 phosphorylation were measured using Western blot analysis. Fasting decreased leptin concentrations in both pregnant and nonpregnant rats. Leptin treatment significantly reduced food intake in nonpregnant and d-7 pregnant rats but not in d-14 pregnant rats. In addition, there was no postfasting hyperphagic response in the pregnant rats. In the pregnant rats, leptin-induced STAT3 phosphorylation was suppressed in the arcuate nucleus and, to a lesser extent, in the ventromedial hypothalamus (VMH), compared with nonpregnant rats. Unstimulated STAT3 levels were also decreased in the VMH during pregnancy. Leptin-induced phosphorylation of STAT3 in the dorsomedial and lateral hypothalamus was not different between pregnant and nonpregnant rats. These data indicate that pregnant rats become resistant to the satiety action of leptin. Furthermore, leptin-induced activation of the STAT3 is impaired during pregnancy, specifically in the arcuate nucleus and VMH. These data support the hypothesis that pregnancy is a state of hypothalamic leptin resistance.

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Evidence for hypothalamic ketone body sensing: impact on food intake and peripheral metabolic responses in mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00282.2015 ◽

2016 ◽

Vol 310 (2) ◽

pp. E103-E115 ◽

Cited By ~ 19

Author(s):

Lionel Carneiro ◽

Sarah Geller ◽

Xavier Fioramonti ◽

Audrey Hébert ◽

Cendrine Repond ◽

...

Keyword(s):

Food Intake ◽

Ketone Body ◽

Energy Homeostasis ◽

Ketone Bodies ◽

Glucose Production ◽

Body Level ◽

Homeostasis Regulation ◽

The Impact ◽

Body Concentration

Monocarboxylates have been implicated in the control of energy homeostasis. Among them, the putative role of ketone bodies produced notably during high-fat diet (HFD) has not been thoroughly explored. In this study, we aimed to determine the impact of a specific rise in cerebral ketone bodies on food intake and energy homeostasis regulation. A carotid infusion of ketone bodies was performed on mice to stimulate sensitive brain areas for 6 or 12 h. At each time point, food intake and different markers of energy homeostasis were analyzed to reveal the consequences of cerebral increase in ketone body level detection. First, an increase in food intake appeared over a 12-h period of brain ketone body perfusion. This stimulated food intake was associated with an increased expression of the hypothalamic neuropeptides NPY and AgRP as well as phosphorylated AMPK and is due to ketone bodies sensed by the brain, as blood ketone body levels did not change at that time. In parallel, gluconeogenesis and insulin sensitivity were transiently altered. Indeed, a dysregulation of glucose production and insulin secretion was observed after 6 h of ketone body perfusion, which reversed to normal at 12 h of perfusion. Altogether, these results suggest that an increase in brain ketone body concentration leads to hyperphagia and a transient perturbation of peripheral metabolic homeostasis.

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Maternal High-Fat–High-Carbohydrate Diet-Induced Obesity Is Associated with Increased Appetite in Peripubertal Male but Not Female C57Bl/6J Mice

Nutrients ◽

10.3390/nu12102919 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2919 ◽

Cited By ~ 1

Author(s):

Debra Kulhanek ◽

Rachel Weigel ◽

Megan E. Paulsen

Keyword(s):

Energy Homeostasis ◽

Maternal Obesity ◽

Maternal Nutrition ◽

Maternal Diet ◽

Critical Role ◽

Caloric Intake ◽

Maternal Weight ◽

High Fat ◽

High Carbohydrate ◽

Nutritional Influences

Diet-induced maternal obesity might play a critical role in altering hypothalamic development, predisposing the offspring to obesity and metabolic disease later in life. The objective of this study was to describe both phenotypic and molecular sex differences in peripubertal offspring energy homeostasis, using a mouse model of maternal obesity induced by a high-fat–high-carbohydrate (HFHC) diet. We report that males, not females, exposed to a maternal HFHC diet had increased energy intake. Males exposed to a maternal HFHC diet had a 15% increased meal size and a 46% increased frequency, compared to the control (CON) males, without a change in energy expenditure. CON and HFHC offspring did not differ in body weight, composition, or plasma metabolic profile. HFHC diet caused decreased hypothalamic glucocorticoid expression, which was further decreased in males compared to females. Maternal weight, maternal caloric intake, and male offspring meal frequency were inversely correlated with offspring hypothalamic insulin receptor (IR) expression. There was a significant interaction between maternal-diet exposure and sex in hypothalamic IR. Based on our preclinical data, we suggest that interventions focusing on normalizing maternal nutrition might be considered to attenuate nutritional influences on obesity programming and curb the continuing rise in obesity rates.

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Recent advances in understanding the role of leptin in energy homeostasis

F1000Research ◽

10.12688/f1000research.24260.1 ◽

2020 ◽

Vol 9 ◽

pp. 451

Author(s):

Heike Münzberg ◽

Prachi Singh ◽

Steven B. Heymsfield ◽

Sangho Yu ◽

Christopher D. Morrison

Keyword(s):

Food Intake ◽

Energy Expenditure ◽

Energy Homeostasis ◽

Critical Role ◽

Early Data ◽

Dynamic Changes ◽

Leptin Signaling ◽

Future Studies ◽

Physiological Adaptations

The hormone leptin plays a critical role in energy homeostasis, although our overall understanding of acutely changing leptin levels still needs improvement. Several developments allow a fresh look at recent and early data on leptin action. This review highlights select recent publications that are relevant for understanding the role played by dynamic changes in circulating leptin levels. We further discuss the relevance for our current understanding of leptin signaling in central neuronal feeding and energy expenditure circuits and highlight cohesive and discrepant findings that need to be addressed in future studies to understand how leptin couples with physiological adaptations of food intake and energy expenditure.

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Deficiency of Irx5 protects mice from diet-induced obesity and associated metabolic abnormalities

10.1101/2021.09.27.462004 ◽

2021 ◽

Author(s):

Joe Son ◽

Kyoung-Han Kim ◽

Chi-chung Hui

Keyword(s):

Food Intake ◽

Body Mass ◽

Energy Homeostasis ◽

Caloric Intake ◽

Mass Composition ◽

Metabolic Abnormalities ◽

Diet Induced Obesity ◽

Body Mass Composition ◽

Polygenic Obesity

Obesity, a leading cause of several metabolic abnormalities, is mainly due to an imbalance of energy homeostasis. IRX3 and IRX5 have been suggested as determinants of obesity in connection with the intronic variants of FTO, the strongest genetic risk factor of polygenic obesity in humans. Although the causal effects of Irx3 on obesity and its related metabolic consequences have been demonstrated in vivo, the metabolic function of Irx5 remains unclear. In this study, using mice homozygous for an Irx5-knockout (Irx5KO) allele, we show a direct link between Irx5 expression and regulation of body mass/composition and energy homeostasis. Irx5KO mice are leaner and resistant to diet-induced obesity and associated metabolic abnormalities, primarily through the loss of adiposity with an increase in basal metabolic rate with adipose thermogenesis and lower food intake. Furthermore, our long-term feeding analysis found that Irx3 mutant mouse lines also have less food intake, indicating that lower caloric intake also contributes to their lean phenotype. Together, these results demonstrate that Irx5 is critical for energy homeostasis and regulation of body mass/composition and suggest that it likely acts in other tissues beyond adipocytes.

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Abstract 053: Uncoupling the Metabolic and Cardiovascular Actions of Leptin through mTORC1 Signaling

Hypertension ◽

10.1161/hyp.66.suppl_1.053 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Balyssa B Bell ◽

Donald A Morgan ◽

Mohamed Rouabhi ◽

Kamal Rahmouni

Keyword(s):

Body Weight ◽

Food Intake ◽

Arterial Pressure ◽

Sympathetic Nerve ◽

Intracellular Signaling ◽

Energy Homeostasis ◽

Critical Role ◽

Conditional Knockout ◽

Mtorc1 Signaling ◽

Nerve Recordings

The adipocyte-derived hormone leptin has a well-established role in the regulation of energy homeostasis, acting in the brain to decrease food intake and promote energy expenditure. Additionally, leptin increases regional sympathetic nerve activity (SNA) and arterial pressure. Multiple intracellular signaling cascades are activated by leptin via its long form receptor (LRb), but the specific roles of these pathways in mediating leptin’s various effects have not been fully understood. Recent evidences suggest that the mechanistic target of rapamycin complex 1 (mTORC1) plays an important role in mediating leptin action. To determine the contribution of mTORC1 to the metabolic and cardiovascular effects of leptin, we generated conditional knockout mice that lack the critical mTORC1 subunit, Raptor, specifically in LRb-expressing cells (LRb Cre /Raptor fl/fl ). Interestingly, body weight was comparable between LRb Cre /Raptor fl/fl mice and controls (29.6±0.8 g vs 31.0±0.8g at 14 weeks of age). Moreover, leptin treatment (1μg/g bw, intraperitoneally, twice daily for 4 days) led to a similar decrease in food intake (-1.6±0.8 g in LRb Cre /Raptor fl/fl mice vs -1.1±1.7 g in controls) and body weight (-5.9±0.8% vs -5.7±0.7%) in both groups. Next, we measured arterial pressure using radiotelemetry at baseline and in response to 2 μg intracerebroventricular (ICV) leptin. Baseline mean arterial pressure (MAP) was comparable between LRb Cre /Raptor fl/fl mice (108±9 mmHg) and controls (103±7 mmHg). However, ICV leptin significantly increased MAP in control mice (30±14 mmHg), but not in LRb Cre /Raptor fl/fl mice (1±9 mmHg, P<0.05 vs controls). The same pattern was observed for systolic and diastolic arterial pressure. Consistent with leptin’s action on MAP, we observed a significant increase in renal SNA in response to ICV leptin in control littermates (106±20%) that was absent in LRb Cre /Raptor fl/fl mice (-28±11%, P<0.05 vs controls) as determined by multifiber sympathetic nerve recordings. Our data suggest a critical role for mTORC1 signaling in mediating the cardiovascular sympathetic but not the metabolic actions of leptin, a dissociation that may have important implications for obesity-associated hypertension.

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Augmented Insulin and Leptin Resistance of High Fat Diet-Fed APPswe/PS1dE9 Transgenic Mice Exacerbate Obesity and Glycemic Dysregulation

International Journal of Molecular Sciences ◽

10.3390/ijms19082333 ◽

2018 ◽

Vol 19 (8) ◽

pp. 2333 ◽

Cited By ~ 8

Author(s):

Yi-Heng Lee ◽

Hao-Chieh Hsu ◽

Pei-Chen Kao ◽

Young-Ji Shiao ◽

Skye Hsin-Hsien Yeh ◽

...

Keyword(s):

Food Intake ◽

Transgenic Mice ◽

High Fat Diet ◽

Energy Homeostasis ◽

Underlying Mechanism ◽

Leptin Resistance ◽

High Fat ◽

Interscapular Brown Adipose Tissue ◽

Positron Emission ◽

Brown Adipose

Alzheimer’s disease (AD), a progressive neurodegenerative disease is highly associated with metabolic syndromes. We previously demonstrated that glycemic dysregulation and obesity are augmented in high fat diet (HFD)-treated APPswe/PS1dE9 (APP/PS1) transgenic mice. In the current study, the underlying mechanism mediating exacerbated metabolic stresses in HFD APP/PS1 transgenic mice was further examined. APP/PS1 mice developed insulin resistance and, consequently, impaired glucose homeostasis after 10 weeks on HFD. [18F]-2-fluoro-2-deoxy-d-glucose ([18F]-FDG) positron emission tomography showed that interscapular brown adipose tissue is vulnerable to HFD and AD-related pathology. Chronic HFD induced hyperphagia, with limited effects on basal metabolic rates in APP/PS1 transgenic mice. Excessive food intake may be caused by impairment of leptin signaling in the hypothalamus because leptin failed to suppress the food intake of HFD APP/PS1 transgenic mice. Leptin-induced pSTAT3 signaling in the arcuate nucleus was attenuated. Dysregulated energy homeostasis including hyperphagia and exacerbated obesity was elicited prior to the presence of the amyloid pathology in the hypothalamus of HFD APP/PS1 transgenic mice; nevertheless, cortical neuroinflammation and the level of serum Aβ and IL-6 were significantly elevated. Our study demonstrates the pivotal role of AD-related pathology in augmenting HFD-induced insulin and leptin resistance and impairing hypothalamic regulation of energy homeostasis.

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The central melanocortin system and human obesity

Journal of Molecular Cell Biology ◽

10.1093/jmcb/mjaa048 ◽

2020 ◽

Author(s):

Yongjie Yang ◽

Yong Xu

Keyword(s):

Body Weight ◽

Food Intake ◽

Energy Expenditure ◽

Genetic Variants ◽

Energy Homeostasis ◽

Critical Role ◽

Human Obesity ◽

Melanocortin System ◽

Prevalence Of Obesity

Abstract The prevalence of obesity and the associated comorbidities highlight the importance of understanding the regulation of energy homeostasis. The central melanocortin system plays a critical role in controlling body weight balance. Melanocortin neurons sense and integrate the neuronal and hormonal signals, and then send regulatory projections, releasing anorexigenic or orexigenic melanocortin neuropeptides, to downstream neurons to regulate the food intake and energy expenditure. This review summarizes the latest progress in our understanding of the role of the melanocortin pathway in energy homeostasis. We also review the advances in the identification of human genetic variants that cause obesity via mechanisms that affect the central melanocortin system, which have provided rational targets for treatment of genetically susceptible patients.

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