Early postnatal interactions between beige adipocytes and sympathetic neurites regulate innervation of subcutaneous fat

While beige adipocytes have been found to associate with dense sympathetic neurites in mouse inguinal subcutaneous white fat (iWAT), little is known about when and how this patterning is established. Here, we applied whole-tissue imaging to examine the development of sympathetic innervation in iWAT. We found that parenchymal neurites actively grow between postnatal day 6 (P6) and P28, overlapping with early postnatal beige adipogenesis. Constitutive deletion of Prdm16 in adipocytes led to a significant reduction in early postnatal beige adipocytes and sympathetic density within this window. Using an inducible, adipocyte-specific Prdm16 knockout model, we found that Prdm16 is required for guiding sympathetic growth during early development. Deleting Prdm16 in adult animals, however, did not affect sympathetic structure in iWAT. Together, these findings highlight that beige adipocyte-sympathetic neurite communication is crucial to establish sympathetic structure during the early postnatal period but may be dispensable for its maintenance in mature animals.

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Adipose tissue-derived neurotrophic factor 3 regulates sympathetic innervation and thermogenesis in adipose tissue

10.1101/2020.06.06.137273 ◽

2020 ◽

Author(s):

Xin Cui ◽

Jia Jing ◽

Rui Wu ◽

Qiang Cao ◽

Fenfen Li ◽

...

Keyword(s):

Adipose Tissue ◽

Neurotrophic Factor ◽

Sympathetic Innervation ◽

Neurite Growth ◽

Sympathetic Neuron ◽

Beige Adipocyte ◽

Diet Induced Obesity ◽

Neurotrophin 3 ◽

Beige Adipocytes ◽

Adipocyte Development

AbstractActivation of brown fat thermogenesis increases energy expenditure and alleviates obesity. Sympathetic nervous system (SNS) is important in brown/beige adipocyte thermogenesis. Here we discover a novel fat-derived “adipokine” neurotrophic factor neurotrophin 3 (NTF3) and its receptor Tropomyosin receptor kinase C (TRKC) as key regulators of SNS growth and innervation in adipose tissue. NTF3 is highly expressed in brown/beige adipocytes, and potently stimulates sympathetic neuron neurite growth. NTF3/TRKC regulates a plethora of pathways in neuronal axonal growth and elongation. Adipose tissue sympathetic innervation is significantly increased in mice with adipocyte-specific NTF3 overexpression, but profoundly reduced in mice with TRKC haploinsufficiency (TRKC+/-). Increasing NTF3 via pharmacological or genetic approach promotes beige adipocyte development, enhances cold-induced thermogenesis and protects against diet-induced obesity (DIO); whereas TRKC+/- mice or SNS TRKC deficient mice are cold intolerant and prone to DIO. Thus, NTF3 is an important fat-derived neurotrophic factor regulating SNS innervation, energy metabolism and obesity.

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Egr1 loss-of-function promotes beige adipocyte differentiation and activation specifically in inguinal subcutaneous white adipose tissue

Scientific Reports ◽

10.1038/s41598-020-72698-w ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Marianne Bléher ◽

Berbang Meshko ◽

Isabelle Cacciapuoti ◽

Rachel Gergondey ◽

Yoann Kovacs ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Adipocyte Differentiation ◽

Uncoupling Protein ◽

Subcutaneous Fat ◽

Loss Of Function ◽

Beige Adipocyte ◽

Subcutaneous White Adipose Tissue ◽

Fat Depots ◽

Beige Adipocytes

Abstract In mice, exercise, cold exposure and fasting lead to the differentiation of inducible-brown adipocytes, called beige adipocytes, within white adipose tissue and have beneficial effects on fat burning and metabolism, through heat production. This browning process is associated with an increased expression of the key thermogenic mitochondrial uncoupling protein 1, Ucp1. Egr1 transcription factor has been described as a regulator of white and beige differentiation programs, and Egr1 depletion is associated with a spontaneous increase of subcutaneous white adipose tissue browning, in absence of external stimulation. Here, we demonstrate that Egr1 mutant mice exhibit a restrained Ucp1 expression specifically increased in subcutaneous fat, resulting in a metabolic shift to a more brown-like, oxidative metabolism, which was not observed in other fat depots. In addition, Egr1 is necessary and sufficient to promote white and alter beige adipocyte differentiation of mouse stem cells. These results suggest that modulation of Egr1 expression could represent a promising therapeutic strategy to increase energy expenditure and to restrain obesity-associated metabolic disorders.

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Egr1 loss-of-function promotes beige adipocyte differentiation and activation specifically in inguinal subcutaneous white adipose tissue

10.1101/2020.06.03.131342 ◽

2020 ◽

Author(s):

Marianne Bléher ◽

Berbang Meshko ◽

Rachel Gergondey ◽

Yoann Kovacs ◽

Delphine Duprez ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Adipocyte Differentiation ◽

Uncoupling Protein ◽

Subcutaneous Fat ◽

Loss Of Function ◽

Beige Adipocyte ◽

Subcutaneous White Adipose Tissue ◽

Fat Depots ◽

Beige Adipocytes

AbstractExercise, cold exposure and fasting lead to the differentiation of inducible-brown adipocytes, called beige adipocytes, within white adipose tissue and have beneficial effects on fat burning and metabolism, through heat production. This browning process is associated with an increased expression of the key thermogenic mitochondrial uncoupling protein 1, Ucp1. Egr1 transcription factor has been described as a regulator of white and beige differentiation programs, and Egr1 depletion is associated with a spontaneous increase of subcutaneous white adipose tissue browning, in absence of external stimulation. Here, we demonstrate that Egr1 mutant mice exhibit a restrained Ucp1 expression specifically increased in subcutaneous fat, resulting in a metabolic shift to a more brown-like, oxidative metabolism, which was not observed in other fat depots. In addition, Egr1 is necessary and sufficient to promote white and alter beige adipocyte differentiation of mouse stem cells. These results suggest that modulation of Egr1 expression could represent a promising therapeutic strategy to increase energy expenditure and to restrain obesity-associated metabolic disorders.

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Neuroendocrine responsiveness to light during the neonatal period in the sheep

Journal of Endocrinology ◽

10.1677/joe.0.1190211 ◽

1988 ◽

Vol 119 (2) ◽

pp. 211-218 ◽

Cited By ~ 14

Author(s):

F. J. P. Ebling ◽

L. E. Claypool ◽

D. L. Foster

Keyword(s):

Sympathetic Innervation ◽

Postnatal Period ◽

Early Postnatal Period ◽

Serum Prolactin ◽

Dark Phase ◽

Night Time ◽

Nocturnal Increase ◽

Cervical Ganglia ◽

Low Amplitude ◽

Short Days

ABSTRACT Circulating prolactin concentrations were monitored during the early postnatal period in sheep to evaluate their response to photoperiod. In the first experiment, male and female lambs were exposed from 1 week of age, with their mothers, to either long days (16 h light:8 h darkness; n = 15) or short days (8 h light:16 h darkness; n = 16) to test whether they could discriminate different day lengths. In both sexes, serum prolactin concentrations were higher on long than on short days during the first 7 weeks after birth. In the second experiment, female lambs (n = 21) were raised on long days from 2 weeks of age. The superior cervical ganglia were removed bilaterally at 4 weeks of age from 14 lambs to lesion the sympathetic innervation to the pineal gland, and thus ablate the nocturnal increase in pineal melatonin secretion. After surgery, serum prolactin concentrations on long days were significantly lower in ganglionectomized lambs than in the intact controls. In the third experiment, the amplitude of the night-time melatonin rise was artificially increased in female lambs (n = 8) between 2 and 7 weeks of age to adult levels. Unrestrained lambs were infused during the 8-h dark phase of each day with melatonin by means of a self-contained, computerized syringe-pump. Concentrations of circulating prolactin did not differ from those in uninfused lambs (n = 8) with lower endogenous nocturnal melatonin. These results reveal that the sheep can discriminate photoperiod cues during the early postnatal period, and suggest that the low-amplitude melatonin rhythm in the neonatal lamb is sufficient to mediate this response. J. Endocr. (1988) 119, 211–218

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Adipose tissue-derived neurotrophic factor 3 regulates sympathetic innervation and thermogenesis in adipose tissue

Nature Communications ◽

10.1038/s41467-021-25766-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Xin Cui ◽

Jia Jing ◽

Rui Wu ◽

Qiang Cao ◽

Fenfen Li ◽

...

Keyword(s):

Adipose Tissue ◽

Neurotrophic Factor ◽

Sympathetic Innervation ◽

Neurite Growth ◽

Sympathetic Neuron ◽

Beige Adipocyte ◽

Diet Induced Obesity ◽

Neurotrophin 3 ◽

Beige Adipocytes ◽

Adipocyte Development

AbstractActivation of brown fat thermogenesis increases energy expenditure and alleviates obesity. Sympathetic nervous system (SNS) is important in brown/beige adipocyte thermogenesis. Here we discover a fat-derived “adipokine” neurotrophic factor neurotrophin 3 (NT-3) and its receptor Tropomyosin receptor kinase C (TRKC) as key regulators of SNS growth and innervation in adipose tissue. NT-3 is highly expressed in brown/beige adipocytes, and potently stimulates sympathetic neuron neurite growth. NT-3/TRKC regulates a plethora of pathways in neuronal axonal growth and elongation. Adipose tissue sympathetic innervation is significantly increased in mice with adipocyte-specific NT-3 overexpression, but profoundly reduced in mice with TRKC haploinsufficiency (TRKC +/−). Increasing NT-3 via pharmacological or genetic approach promotes beige adipocyte development, enhances cold-induced thermogenesis and protects against diet-induced obesity (DIO); whereas TRKC + /− or SNS TRKC deficient mice are cold intolerant and prone to DIO. Thus, NT-3 is a fat-derived neurotrophic factor that regulates SNS innervation, energy metabolism and obesity.

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Serum Nitrogenous Compounds in Piglets during the Early Postnatal Period

Journal of Animal Science ◽

10.2527/jas1970.313531x ◽

1970 ◽

Vol 31 (3) ◽

pp. 531-534 ◽

Cited By ~ 1

Author(s):

S. Gösta Bengtsson

Keyword(s):

Postnatal Period ◽

Early Postnatal Period ◽

Nitrogenous Compounds

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Faculty Opinions recommendation of Irreversible triggers for hypertrophic cardiomyopathy are established in the early postnatal period.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725357974.793535817 ◽

2017 ◽

Author(s):

WH Wilson Tang

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Postnatal Period ◽

Early Postnatal Period

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Beige adipocytes mediate the neuroprotective and anti-inflammatory effects of subcutaneous fat in obese mice

Nature Communications ◽

10.1038/s41467-021-24540-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

De-Huang Guo ◽

Masaki Yamamoto ◽

Caterina M. Hernandez ◽

Hesam Khodadadi ◽

Babak Baban ◽

...

Keyword(s):

Subcutaneous Fat ◽

Visceral Obesity ◽

Interleukin 4 ◽

Hippocampal Synaptic Plasticity ◽

Beige Adipocytes ◽

Beige Fat ◽

Dietary Obesity ◽

Anti Inflammatory ◽

Subcutaneous Adiposity ◽

The Relationship

AbstractVisceral obesity increases risk of cognitive decline in humans, but subcutaneous adiposity does not. Here, we report that beige adipocytes are indispensable for the neuroprotective and anti-inflammatory effects of subcutaneous fat. Mice lacking functional beige fat exhibit accelerated cognitive dysfunction and microglial activation with dietary obesity. Subcutaneous fat transplantation also protects against chronic obesity in wildtype mice via beige fat-dependent mechanisms. Beige adipocytes restore hippocampal synaptic plasticity following transplantation, and these effects require the anti-inflammatory cytokine interleukin-4 (IL4). After observing beige fat-mediated induction of IL4 in meningeal T-cells, we investigated the contributions of peripheral lymphocytes in donor fat. There was no sign of donor-derived lymphocyte trafficking between fat and brain, but recipient-derived lymphocytes were required for the effects of transplantation on cognition and microglial morphology. These findings indicate that beige adipocytes oppose obesity-induced cognitive impairment, with a potential role for IL4 in the relationship between beige fat and brain function.

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