1. Obesity is a major global health problem that impacts quality of life and disease outcomes. The current scenario can be described as "the obese-obese world".
2. The hypothalamus normally regulates energy homeostasis and appetite through integrating metabolic signals, but obesity disrupts these signals. This leads to imbalanced reward pathways and overriding stimulus to eat.
3. Factors like neuroinflammation, oxidative stress, and lipotoxicity converge on stress and inflammatory pathways in the brain, impairing metabolic regulation and neuronal function in areas like the hypothalamus. This neurodegeneration contributes to further dysregulation of appetite and weight gain.
4. The flow of the talk:
1. Normal CNS Regulation of Homeostasis
2. Aberrant CNS Signals & Other Factors
3. The Fallout on Hypothalamus and Other
CNS Structures
5. ‘THE OBESE-OBESE WORLD’
Obesity is a huge health problem of immense magnitude around
the Globe due to Overnutrition and SALS.
Incapacitates QOL and alters course of various chronic diseases.
High potency risk factor for DM, HTN, CVD and stroke,
neurodegenerative diseases and various cancers.
Current health scenario can be summed up as ‘the obese-obese
world’.
7. CNS REGULATION OF ENERGY HOMEOSTASIS
Specialised neurons in hypothalamus and brainstem regulate energy
homeostasis, food intake and body weight through integrating
multiple peripheral metabolic inputs, such as nutrients, gut-derived
hormones, and adiposity-related signals.
Reward circuitry is also involved and interactions between
Receptors and NTMs - opioids, endocannabinoids, serotonin and
dopamine. Gets altered, leading to imbalanced reward seeking.
Further, the altered cognitive control leads to an overriding stimulus
to feeding, even in the absence of an energy deficit.
8. Neuropeptides are involved, including MCH and the orexins. The altered
ghrelin and leptin levels due to increase in adiposity leads to overproduction
of leptin and hypothalamus becomes resistant to leptin action.
THE CNS REGULATION OF APPETITE AND MEAL SIZE
Fig 2. Physiology of Appetite Regulation
9. With obesity, there is impaired vascular reactivity,
endothelial dysfunction, neuro-inflammation, oxidative
stress and altered brain metabolism.
There may occur atrophy in frontal lobes, anterior cingulate
gyrus, hippocampus and thalamus. MetS affects cognitive
domains including executive functioning, processing speed
and overall intellectual functioning in those with BMI > 30 .
The aberrancy of CNS signals means that the normal
physiology of appetite regulation is disturbed along with
metabolic homeostasis, energy balance along with humoral
feedback.
10. REGULATION OF ENERGY EXPENDITURE BY CNS
Energy is spent in basic metabolic processes, adaptive
thermogenesis and physical activity – modulated by brain ,
especially hypothalamic melanocortin system.
BAT has major role in thermogenesis, which is regulated by CNS
through sympathetic outflow to BAT. Norepinephrine released from
sympathetic nerve endings binds to B-3 adrenergic receptors on BAT
and promotes enhanced thermo-adrenergic receptor-ogenesis.
In addition, various hormonal and nutrient signals, such as glucose,
insulin, leptin and GLP-1 also influence sympathetic outflow to BAT.
12. HYPOTHALAMIC REGULATION OF ENERGY HOMEOSTASIS
Hypothalamus is regulator of Circadian Clock, ANS and Hormonal
secretion. It has neural centres for regulation of thirst and hunger.
It communicates with other regulatory centres in Prefrontal and
Insular cortices, Amygdala and other limbic structures, Midbrain,
Pons, Medulla and Vagus and GP nerves.
AN contains Orexigenic neurons co-expressing AGRP/NPY and
Anorexigenic neurons co-expressing POMC and CART. Being
located outside BBB, it can sense inputs from circulating nutrients
and hormones.
The AGRP/NPY neurons enhance appetite by GABA-mediated
tonic inhibition of POMC/CART neurons and suppression of
anorexigenic signals from Parabrachial nucleus of Pons. The
Anorexigenic inputs come from Glutaminergic signals originating
in NTS in Medulla.
13. OTHER BRAIN AREAS FOR REGULATION OF ENERGY
HOMEOSTASIS
Area Postrema in Brainstem receives and integrates multiple metabolic signals,
including Anorexigenic signals from Leptin, Cholecystokinin, Amylin, GLP-1, PP and
PYY, and Orexigenic signals from Ghrelin,
This Area projects to NTS, which receives input from Vagal afferent fibres located
in GIT, and relays signals to PBN in Pons, which in turn relays Anorexigenic signals
to AN and Central Amygdala.
GLP-1 expressing neurons in NTS relay Anorexigenic signals to CRH, Nefstatin-1
and Oxytocin expressing neurons in PVN. BDNF receptors, TrkB, expressed in Area
Postrema, NTS and Dorsal motor nucleus of Vagus, mediate Anorexigenic effects
of Brainstem BDNF.
Taste sensation is mediated in part by nuclei located in Central Amygdala. Smell
sensation is also important. Food reward signals are mediated by Midbrain
Dopaminergic neurons projecting to Limbic system and Prefrontal Cortex.
14. THE ALTERED CNS REGULATION FOR
METABOLIC HOMEOSTASIS
With weight gain, ability of Hypothalamus to regulate energy balance is
altered. The aberrant functioning appears at multiple levels – Integration
of satiety signals and Regulation of Glucose and Lipid Metabolism. In
addition, Adiposity related inflammatory response alters Functioning of
various Hypothalamic nuclei.
There occur Reduced synapses in POMC neurons and failure of Leptin to
inhibit Orexigenic effects of AGRP neurons. There is impairment of
Anorexigenic signals in Caudomedial nucleus of NTS and Altered
Circadian Clock.
SALS in setting of obesity is associated with reduced Dopamine signaling
in Meso-Accumbens Dopamine system. Hedonic eating, i.e., consumption
of papatable foods beyond need-based energy requirements, is its
fallout.
15. MULTIVARIATE FACTORS IN ABERRANT REGULATION
Energy balance and Body weight are regulated by CNS, by sensing metabolic
status from various humoral and neural signals and controlling energy intake. In
Hypothalamus, stimulation of Leptin- and Ghrlin- responsive pathways, including
Central Melanocortin system, contribute to maintenance of nearly stable Adipose
tissue amount and Body weight.
CNS Melanocortin system is mediator of Central effects of Leptin – Reduced
activity of CNS-MC system promotes obesity. Circulating Leptin levels correlate
with adiposity and there is associated Leptin resistance. Whereas, Ghrelin having
appetite-inducing effect and obese subjects have lower Ghrelin levels.
CNS significantly regulates adipose tissue mass by acting on metabolic pathways
and adipose plasticity. Innervation by autonomic nerves modulates glucose and
lipid metabolism in adipose tissue. And adipose tissue functions at cellular and
molecular levels. In general, sympathetic NS is related to catabolism and
parasympathetic NS to anabolism.
16. MULTIVARIATE FACTORS IN ABERRANT ..2
FIG 4: THE LIPOTOXICITY AND ITS FALLOUTS
Increased release of proinflammatory cytokines, including TNF-α, is a key
feature of pathophysiology of metabolic disorders associated with adiposity.
In Brain, TNF-α is secreted by microglial cells.
17. MULTIVARIATE FACTORS IN ABERRANT ..3
Adiposity and Lipotoxicity cause deterioration of metabolic regulation by
converging on Inflammatory and Stress Pathways.
Lipotoxicity → ROS production from mitochondria and Inflammasome activation
→ Synthesis of DAGS and Ceramides → DAGS activate Stress Kinases, PKCS and
NFKB pathways, and Ceramides activate JNK signaling. Both, DAGS and Ceramides
cause Insulin resistance via inhibition of IRS1 and AKT, respectively.
Activation of TLR4 signaling → Activation of Inflammasomes and induction of
Inflammatory Gene Transcription factors, Interferon regulatory factor (IRF), NFKB
and AP-1.
Accumulation of oxidized cholesterol or cholesterol crystals also lead to
induction of TLR4, PKR and Sress kinases (JNK and P38) signaling, inflammasome
activation and Proinflammatory gene expression – central players in
atherosclerosis progression.
18. MULTIVARIATE FACTORS IN ABERRANT ..4
Adiposity and inflammatory changes lead to dysregulated lipid synthesis in ER,
leading to disruption of Ca+ signaling, ER stress and decreased translation of ER-
associated proteins.
ER stress responses intersect with inflammatory pathways via activation of
inflammatory kinases, such as JNK, PKR and IKK, and activation of inflammatory
mediators and inflammasome., leading to meta-inflammation.
Adiposity, Neuroinflammation and neurodegenerative disorders are linked by
alterations in molecular pathways such as P13K/AKT signaling pathway and IKKB/NF-
KB pathway, which lead to altered gene expression profiles and activate or deactivate
molecular mediators, heralding abnormal cellular functioning.
Concomitant with these alterations are Oxidative damage to cellular components and
increased secretion of proinflammatory factors like TNF-α, cytokines and
interleukins, and altered CNS signals involving multiple metabolic pathways.
19. .
Adiposity affects Glucose and Energy metabolism of Brain cells and through increased secretion of
proinflammatory agents like TNF-α, IL-1 and IL-6 induces Neuroinflammation primarily in
Hypothalamic area, leading to neuronal impairment.
NEUROINFLAMMATION AND NEURODEGENERATION
Fig 5: Multivariate Factors and Neuro-Inflammation-Degeneration
20. THE IMPAIRED GLUCOSE HOMEOSTASIS
AND CNS ALTERATIONS
Impaired Glucose Tolerance is a factor leading to Neurodegenerative
disorders. Insulin holds the neurotrophic property for neuro-cells, its effects
mediated by insulin receptors, mostly localized in Hippocampus, Entorhinal
and Frontal Cortices.
Adiposity causes IR, which in turn leads to Glucose intolerance, affecting
Membrane cation transport. Insulin deficiency and resistance trigger
neurodegeneration and neuronal death due to deficient trophic factor, energy
metabolic deficits and impaired insulin-responsive gene expression.
Neurons cannot synthesize or store glucose, it has to be transported across
the BBB, which is done by glucose transporters. With glucose dysmetabolism,
AGEs start accumulating within the cells, leading to neuronal dysfunction and
neurodegeneration.
21. THE INITIATION AND SUSTENANCE OF
NEUROINFLAMMATION
Adiposity brings about a state of systemic inflammation as hypertrophied
adipocytes and immune cells in adipose tissue lead to increased circulating
levels of proinflammatory cytokines, such as TNF-α, IL-1, IL-6 and IL-8, which
damage neurons and neuronal circuits. Hypothalamus is significantly
affected by neuroinflammation.
Out of over 50 adipokines, Adiponectin and Autotaxin play predominant
role in neurodegeneration. Leptin is neuroprotectant against OxS and
cytotoxicity. Leptin signaling is decreased in Arcuate nucleus in obesity.
Neuroinflammation is activation of innate immune response of brain tissue
for protection against infection, trauma or disease. It encompasses series of
reactions consisting of cellular and molecular changes, initiation of
intracellular signaling pathways and release of inflammatory mediators
leading to neuronal dysfunction and loss.
22. THE INITIATION AND SUSTENANCE
OF NEUROINFLAMMATION ..2
Insulin and IGF-1 play important role in Brain Glucose Homeostasis. In
physiological conditions, insulin receptors (IRS/IGF-1RS) are activated in
response to OxS, whereas Glycogen Synthase-kinase (GSK-3B) is inhibited.
Accompanied by increased production of 4-Hydroxynonenal (4-HNE) for
oxidative protection of neuronal lipids and proteins.
Neuroinflammation is accompanied by ER stress and Autophagy defects.
Various altered pathways impair neural physiology and cause further
neuronal damage through OxS, ER stress and mitochondrial dysfunction.
The hypothalamic inflammation leads to IR and Glucose intolerance. With
impaired Insulin/IR and IGF-1/IGF-1R signaling, the results are
detrimental.
.
23. THE INITIATION AND SUSTENANCE
OF NEUROINFLAMMATION ..3
Further, inflammatory processes involve activation of IKKB/NF-KB
pathway. The hypothalamic inflammation induced by the IKKB/NF-
KB pathway leads to insulin resistance and glucose intolerance.
The abnormal IKKB pathway degrades IKB protein and liberates NF-
KB which localizes to nucleus and activates transcription of
inflammatory proteins. Toll-like Receptors (TLRS) and cytokine
receptors are involved in this process.
The deranged and aberrant CNS signals as the result of Adipotoxicity
and lipotoxicity, thus, end up in neuro-meta-inflammation and
impaired neuronal function and finally, neuronal degeneration.
Editor's Notes
This my hospital and research institute in New Delhi, India. A over one-thousand bedded tertiary care set-up.
As you can see it’s huge – an arena of multiple buildings, sophisticated as par with other large hospitals in Delhi
and highly crowded.
melanin concentrating hormone (MCH)
Brown adipose tissue (BAT)
GP = Glossopharyngeal
pancreatic peptide (PP) Peptide YY (PYY) Parabrachial nucleus (PBN) in the pons, corticotrophin-releasing hormone (CRH),