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Printable Handouts
Navigable Slide Index
- Introduction
- What is neuroimmunometabolism?
- What we will cover today?
- Metabolism
- What regulates fat mass?
- Leptin action is not solely mediated by suppression of food intake
- How does leptin cause weight loss beyond suppression of food intake?
- The neuroendocrine loop of leptin action
- Tissue clearing techniques
- Sympathetic innervation of the iWAT
- Sympathetic neuro-adipose junctions
- Sympathetic neuro-adipose junctions: optogenetics
- Optogenetic stimulation drives NE release and lipolysis (1)
- Optogenetic stimulation drives NE release and lipolysis (2)
- Development of a drug for obesity
- Genetic sympathectomy mediates fast and irreversible obesity, independent of food intake
- Leptin-driven lipolysis
- The neuroendocrine loop of leptin beyond suppression food intake
- Leptin resistance in obesity
- The discovery of SAMs
- Sympathetic Associated Macrophages (SAMs)
- SAMs: RNAseq
- SAMs are more pro-inflammatory than ATMs
- SAMs express adrenergic genes
- SAM function?
- Studying SAMs in vitro
- SAMs do not have the machinery to synthesize NE
- SAMs can uptake and degrade NE
- SAMs import NE via NET (Slc6a2) to limit extracelluar NE
- SNS activation increases SAM inflammation
- Obesity increases SAMs
- Can obesity be reverted by LoF of SAMs?
- Looking for LoF tools or Cre drivers
- SAMs have Slc6a2, unlike other hematopoietic cells
- LoF of Slc6a2 leads to browning and thermogenesis
- LoF of Slc6a2 in SAMs leads to sustained weight loss independent of food intake
- Do SAMs exist in humans?
- Human SAMs
- Human SAMs: Slc6a2 and MAOa staining
- Macrophages can metabolise NE
- SAMs contribute to obesity by importing and metabolising NE
- Amphetamine
- Chemically modify AMPH to avoid the brain
- PEGyAMPH is brain-impermeable
- PEGyAMPH does not induce hyperkinesia and hypophagia
- PEGyAMPH facilitates SNS activity (1)
- PEGyAMPH facilitates SNS activity (2)
- PEGyAMPH defends against diet-induced obesity
- PEGyAMPH increases WAT NE and lipolysis
- PEGyAMPH reduces adipose mass
- PEGyAMPH increases energy expenditure (EE)
- PEGyAMPH increases thermogenesis
- PEGyAMPH increases thermal dissipation and prevents hyperthermia
- Thermogenesis coupled to heat dissipation
- PEGyAMPH doesn't increase HR or BP
- Cardiac side effects of AMPH are triggered by the brain
- Sympathofacilitators
- Sympathofacilitators bypass leptin resistence
- Acknowledgements
- Funding
Topics Covered
- What is neuroimmunometabolism
- Metabolism
- Regulation of adiposity by leptin
- Neuroendocrine loop of leptin action
- Stimulation of sympathetic neurons drives NE release and lipolysis
- Sympathetic neuron associated macrophages (SAMs)
- SAMs import and metabolise NE
- Anti-obesity drugs
- Sympathofacilitators bypass leptin resistance
Links
Series:
Categories:
Therapeutic Areas:
Talk Citation
Domingos, A. (2023, October 31). Neuroimmunometabolism [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved December 3, 2024, from https://doi.org/10.69645/KWUM3436.Export Citation (RIS)
Publication History
Financial Disclosures
- No commercial/financial matters to disclose.
Other Talks in the Series: The Immune System - Key Concepts and Questions
Transcript
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0:00
Hello. My name is
Ana Domingos and I
am a professor of neuroscience
in the Department of Physiology,
Anatomy, and Genetics at
the University of Oxford.
The title of this talk is
Neuroimmunometabolism.
0:16
Neuroimmunometabolism
sounds a bit like
a German composite word in
which the words neuroscience,
immunology, and metabolism
are concatenated.
In this intro slide,
those three words are
conveniently color coded,
bringing to your attention,
sympathetic neurons in red which
are populated by immune cells in
green and both of which in turn
control the blue cells,
which are adipocytes.
Adipocytes are central to
the regulation of
metabolism and body weight.
0:46
What are we going
to cover today?
I will start with
the basic concept
in metabolism, for instance,
how leptin regulates body
weight and the primary evidence
supporting that leptin effect on
weight loss goes beyond
suppression of food intake.
I'll go over the discovery of
sympathetic neurons
in fat that are
the efferent arm in the
neuroendocrine loop of
leptin action by
decreasing fat mass.
I'll finally introduce the
concept of leptin resistance
and motivate the search for
biological mechanisms
outside of the brain.
Next, I'll delve into near
immunity by guiding you
through the experiments
that led to the discovery of
sympathetic neuron associated
macrophages that we often
call SAMs and how SAMs
contribute to obesity by
weakening the efferent arm in
the neuroendocrine
loop of leptin action.
Finally, I will talk about
potential anti-obesity
drugs that
capitalize on the
neuroimmunometabolic concepts
described in the
previous sections.
Namely, I'll talk
about the concept of
a sympathofacilitator
drug class that rescues
the weakened efferent arm in
the neuroendocrine loop
of the leptin action.