Food Perception Primes Hepatic ER Homeostasis via Melanocortin-Dependent Control of mTOR Activation

Brandt, Claus; Nolte, Hendrik; Henschke, Sinika; Ruud, Linda Engström; Awazawa, Motoharu; Morgan, Donald A.; Gabel, Paula; Sprenger, Hans‐Georg; Hess, Martin W.; Günther, Stefan; Langer, Thomas; Rahmouni, Kamal; Fenselau, Henning; Krüger, Marcus; Brüning, Jens C.

doi:10.1016/j.cell.2018.10.015

Cited by 94 publications

(98 citation statements)

References 92 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These findings also provide evidences for the crucial role of cephalic phase in regulating metabolism. Sensory perception of food by visual, auditory, and olfactory systems induces heart rate and increases the secretion of digestive enzymes even before ingestion 55 . These responses known as cephalic phase enable efficient nutrient intake and metabolic adaptation, through modulating specific hypothalamic neurons and consequently priming physiological responses in peripheral organs 55,56 .…”

Section: Discussionmentioning

confidence: 99%

Olfactory specificity regulates lipid metabolism through neuroendocrine signaling in Caenorhabditis elegans

et al. 2020

View full text Add to dashboard Cite

Olfactory and metabolic dysfunctions are intertwined phenomena associated with obesity and neurodegenerative diseases; yet how mechanistically olfaction regulates metabolic homeostasis remains unclear. Specificity of olfactory perception integrates diverse environmental odors and olfactory neurons expressing different receptors. Here, we report that specific but not all olfactory neurons actively regulate fat metabolism without affecting eating behaviors in Caenorhabditis elegans, and identified specific odors that reduce fat mobilization via inhibiting these neurons. Optogenetic activation or inhibition of the responsible olfactory neural circuit promotes the loss or gain of fat storage, respectively. Furthermore, we discovered that FLP-1 neuropeptide released from this olfactory neural circuit signals through peripheral NPR-4/neuropeptide receptor, SGK-1/serum-and glucocorticoid-inducible kinase, and specific isoforms of DAF-16/FOXO transcription factor to regulate fat storage. Our work reveals molecular mechanisms underlying olfactory regulation of fat metabolism, and suggests the association between olfactory perception specificity of each individual and his/her susceptibility to the development of obesity.

show abstract

Section: Discussionmentioning

confidence: 99%

Olfactory specificity regulates lipid metabolism through neuroendocrine signaling in Caenorhabditis elegans

et al. 2020

View full text Add to dashboard Cite

show abstract

“…We surmise that 17α-E2 is likely signaling in both the hypothalamus and liver, which is aligned with previous reports demonstrating significant crosstalk between the hypothalamus and liver to regulate metabolic homeostasis. It is well documented that the arcuate nucleus (ARC) of the hypothalamus is a critical region for regulation of hepatic gluconeogenesis through autonomic regulation and vagus nerve activity [56,[77][78][79]. Multiple neuronal populations within the hypothalamus known to be involved in the regulation of systemic metabolism, including Pomc [80], AgRP/NPY [81], and Kisspeptin neurons [82].…”

Section: Discussionmentioning

confidence: 99%

Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α

Mann

Hadad

Nelson-Holte

et al. 2020

Preprint

View full text Add to dashboard Cite

Aging is the greatest risk factor for most chronic diseases. Metabolic dysfunction underlies several chronic diseases, which are further exacerbated by obesity. Dietary interventions can reverse metabolic declines and slow aging processes, although compliance issues remain paramount due to adverse effects on quality of life.17α-estradiol treatment improves metabolic parameters and slows aging in male mice. The mechanism by which 17α-E2 elicits benefits remain unknown, which has led speculation that an uncharacterized receptor is involved. Herein, we show that 17α-estradiol and 17β-estradiol elicit similar genomic binding and transcriptional activation of ERα and that the ablation of ERα in male mice completely attenuates the beneficial effects of 17α-estradiol. Our findings also suggest that 17α-E2 acts primarily through the liver and/or hypothalamus to elicit benefits, and that 17α-E2 also improves metabolic parameters in male rats. Collectively, these data suggest ERα is a relevant drug target for mitigating chronic diseases in male mammals. KEYWORDS17α-estradiol, aging, estrogen receptor, hypothalamus, liver, metabolism, obesity Aging is the leading risk factor for most chronic diseases, many of which are associated with declines in metabolic homeostasis [1]. Metabolic detriments associated with advancing age are further exacerbated by obesity [2,3], which has risen substantially in the older population (> 65 years) over the past several decades [4,5]. Moreover, obesity in mid-life has been shown to accelerate aging mechanisms and induce phenotypes more commonly observed in older mammals [6][7][8][9][10][11][12]. These observations have led many to postulate that obesity may represent a mild progeria syndrome [13][14][15][16][17]. Although it is well established that dietary interventions, including calorie restriction, can reverse obesity-related metabolic sequelae, many of these strategies are not well tolerated in older patients due to concomitant comorbidities [2,18]. Compliance issues across all age groups also remain a paramount hurdle due to calorie restriction adversely affecting mood, thermoregulation, and musculoskeletal mass [19]. These adverse health outcomes demonstrate the need for pharmacological approaches aimed at curtailing metabolic perturbations associated with obesity and aging.17α-estradiol (17α-E2) is one of the more recently studied compounds to demonstrate efficacy for beneficially modulating obesity-and age-related health outcomes. The NIA Interventions Testing Program (ITP) found that long-term administration of 17α-E2 extends median lifespan of male mice in a dose-dependent manner [20,21]. Our group has been exploring potential mechanisms by which 17α-E2 may improve healthspan and extend lifespan in a sex-specific manner. We have found that 17α-E2 administration reduces food intake and regional adiposity in combination with significant improvements in a multitude of systemic metabolic parameters in both middle-aged obese and old male mice without inducing deleterious effects [22][23...

show abstract

“…In addition, the list of metabolic signals regulating nutrient partitioning is growing with the discovery of novel regulators harbouring potent glucose-lowering properties, including fibroblast growth factors 1 and 19 [79][80][81]. Finally, the central control of nutrient partitioning may also rely on external food cues and the pre-absorptive anticipatory phase (cephalic phase), which prime endocrine and metabolic organs for nutrient intake via the ANS [82]. This is a growing and exciting field of research that will potentially open up novel therapeutic avenues for obesity and diabetes.…”

Section: Resultsmentioning

confidence: 99%

Neuronal control of peripheral nutrient partitioning

2020

View full text Add to dashboard Cite

The appropriate utilisation, storage and conversion of nutrients in peripheral tissues, referred to as nutrient partitioning, is a fundamental process to adapt to nutritional and metabolic challenges and is thus critical for the maintenance of a healthy energy balance. Alterations in this process during nutrient excess can have deleterious effects on glucose and lipid homeostasis and contribute to the development of obesity and type 2 diabetes. Nutrient partitioning is a complex integrated process under the control of hormonal and neural signals. Neural control relies on the capacity of the brain to sense circulating metabolic signals and mount adaptive neuroendocrine and autonomic responses. This review aims to discuss the hypothalamic neurocircuits and molecular mechanisms controlling nutrient partitioning and their potential contribution to metabolic maladaptation and disease.

show abstract

Food Perception Primes Hepatic ER Homeostasis via Melanocortin-Dependent Control of mTOR Activation

Cited by 94 publications

References 92 publications

Olfactory specificity regulates lipid metabolism through neuroendocrine signaling in Caenorhabditis elegans

Olfactory specificity regulates lipid metabolism through neuroendocrine signaling in Caenorhabditis elegans

Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α

Neuronal control of peripheral nutrient partitioning

Contact Info

Product

Resources

About