LECTURE 1012 PSYCH 3F03
Lecture 10
January 28, 30 2014
How is Insulin resistance triggered?
− During infection, cytokines trigger insulin resistance
− Inhibit insulin receptors on selected tissues
− Thus, the signaling power of insulin is decreased in those tissues
o Less glucose is taken from the bloodstream
− Resistance in the spleen would not occur, because it is needed in the immune system
Why can your diet trigger the immune system?
− Mechanistically, glucose is the preferred energy source of the immune system
− Immune system must regulate allocation of energy
− Commensal gut bacteria do not elicit an immune response
− Pathogenic bacteria pass through the epithelial barrier and activate TLR dependent immune cascades, but commensals do not
Not all aspects of the diet trigger immune response
− What seems to be important in modern diets that trigger immune response – sugars (glucose), some fatty acids (saturated, not unsaturated)
o Saturated fatty acids are more likely to come from animal products; unsaturated fatty acids from plants
Why do we store fat in adipose tissue?
− Energy reserve for
o Starvation
o Infection
o Pregnancy
o Other conditions of energetic stress
− During energetic stress – fat mobilized and converted into saturated fatty acids (FAs) for the body to use
o Not only fat that is mobilized; glucose from the liver is also mobilized during energetic stress
Immune response is energetically expensive
− Inactive immune system consumes about 23% of overall metabolism (large amount!)
− When activated by infection, increases even further
o Sepsis > 50%
− Where does energy come from is we’re not eating?
o Glucose stored in liver and fatty acids released from adipose tissue
o Less overall food consumption when sick – so where does energy come from?
o Fatty acids stored in adipose tissue and glucose in liver
Lymph nodes are important in the immune response
− Found all over the body
− Often concentrated in regions where pathogens are likely to be encountered
o Eg/ oral cavity, tonsils, digestive tract, genitals – but also in peripheral limbs
− Embedded in adipose tissue – less likely to compete for energy with other tissues
Mobilization of fat and insulinresistance
− Immune response to infection requires both:
o Down regulation of energy expenditure in nonessential tissues
o Mobilization of fat
− Mobilization of fat and insulinresistance should cooccur together – in response to infection, mobilization of fat
and glucose, released into bloodstream, uptaken by certain organs – do not want organs not involved in immune response to take fat and glucose,
only organs involved
Hypothesis
− Presence of saturated fatty acids and glucose in the bloodstream may:
o Signal infection
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o Activate immune pathways
o Trigger insulinresistance
− Saturated fatty acids may be present due to diet from animal sources
o In evolutionary environments
Consumed with animal protein
Wild animals leaner, so lower levels of saturated FAs?
o Modern environments
Intake of saturated FAs without protein
Intake also associated with carbs – mimics infection
Is there any evidence that saturated FA’s and insulinresistance are linked?
− Saturated FA’s activate tolllike receptor 4 (TLR4)
o Immune signaling
− TLR4 plays an important role in promoting insulinresistance
o Free Fatty Acids can activate TLR4 in a complicated pathway that triggers insulin resistance
o Sat FA’s trigger insulin resistance through the activation of TLR4
Insulin resistance in response to dietary intake
− Insulin resistance may occur in a time of feasting, so that carbs turn into fat to be stored in the body
Diabetes and the Immune System
− Diabetes characterized by dysregulated immune system
− More susceptible to disease
− Does the immune system develop insulin resistance under chronically highenergy diets?
o Tentatively, yes
o Dampen immune system in response to high energy diet
o Increased energy, but no infection ▯decrease energy being devoted to immune system – trigger insulin
resistance in immune system
− Hyperglycemia impairs the immune system
o Turnia et al (2005)
− TLR4 receptors found on many immune cells
o Muzio et al (2000)
Lecture 11 – The Hygiene Hypothesis
January 30, 2014
Review: Hypothesis (IR)
− During infection, FA’s and glucose released into bloodstream to fuel immune response
o Insulinresistance in nonimmune tissues
− When you eat a highcarb diet, high saturated FA meal, they get into bloodstream
o Possibly makes body believe it has an infection, triggering insulin resistance in nonimmune tissues, and activating immune system
o May help immune system in dealing with infection if this occurred rarely – effect would be to activate immune system with energy
− Over time, body eventually realizes no infection and dampens immune response
o Obesity and diabetes associated with lowered immune function – disregulated, impaired immune responses;
o If diet is persistently high in glucose and saturated FAs – IR occurring in immune tissues
− Insulin resistance may still be functional – immune system that is affected
Definitions
− Atopic = allergic diseases
− Autoimmune Disease = body’s immune system attacks healthy body tissues
Hay Fever and Family Size
− Strachan 1989
− The National Child Development Study
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− 17,414 British children born during one week in March 1958
− Followed up at ages 7, 11 and 23:
o Age 23 – hay fever in the last 12 months
o Age 11 – parental report of hay fever or allergic rhinitis in the past 12 months
o Age 7 – parental recall of whether child had eczema in the first year of life
− Table
o Risk of hay fever decreased as the number of siblings in the household increased
o Similar results for eczema prevalence
o Highest prevalence for hay fever and eczema when 0 siblings; lowest at 4+ siblings
− These observations do not support suggestions that viral infections, particularly of the respiratory tract, are important precipitants of the expression
of atopy
− Observations could be explained if allergic diseases were prevented by infection in early childhood transmitted by unhygienic contact with older
siblings, or acquired prenatally form a mother infected by contact with her older children
− Over the past century declining family size, improvements in household amenities and higher standards of personal cleanliness have reduced the
opportunity for cross infection in young families
− This may have resulted in more widespread clinical expression of atopic disease, emerging earlier in wealthier people as seems to have occurred for
hay fever
− Seroni, Clerici paper – children who go to day care, have large families or grew up in rural vs. urban settings also have a decreased risk of allergies
Studies
− Study of allergies in 3 different groups
o Waorani – HG tribe that lives in Ecuador; hunting
o Tibetens
o People living in North Carolina – make living by foraging through strange boxes that are refrigerated in houses (?)
− Pollen Allergies in the Waorani Indians
o Skin tests done with plant compounds
o Waorani – 1.4% incidence of allergy developed
o North Carolina – 11.2%
− Asthma in Waorani, Tibet and N. Carolina
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o Used methacholine – positive response (mm that the flare occurs) shows greater asthmalike qualities
o Greater than the plant test because they couldn’t match the exact symptoms
o NC (4.49) > Tibet (.06) > Waorani (less than 1.00)
− Suggests that people living in more traditional environments are less subject to allergies
− Not a lot of studies re: pathogen exposure to HG groups
− Prevalence of endoparasites in the Hiwi (Hurtado et al, 1997)
o Measured parasite load in women and men
o Necator – “hookwork”
Highly prevalence; reaching over 90% of all people
o Ascaris – “roundworm”
o Trichoris – “whipworm”
o Entamoeba – amoebic dysentery
− What about the prevalence of allergies in the Hiwi?
o Allergic sensitization among the Hiwi appears to be negligible
o It may be argued that some of the allergens were tested were foreign to the Hiwi (eg/ the house dust mite, Dermatophadoides farniae)
o That was not the case for most of the allergens – molds are ubiquitous and leguminosae pollen is airborne and widely dispersed in the
tropics
o Sources of house dust and “aeroallergen” were local
o Ascaris exposure may still be relevant, in spite of the relatively low Ascaris prevalence we found
o All these allergens failed to elicit reaction sin 17/18 subjects
o Only 1/18 developed allergy
o Not conclusive evidence that exposure to pathogens protects against allergies
− Why is exposure to pathogens thought to protect against allergies? No one knows ▯Tcells? Original thought:
o Th1 and Th2 cells
Immune response to viral/bacterial infections involves Th1
• Macrophage activity
• Antibody production
Parasitic worms trigger Th2 cell responses
o Hypothesized that if not exposed to pathogens – may cause overactive immune system
o Overactive Th1 ▯autoimmune disorders
o Overactive Th2 ▯allergic disorders
o Need exposure to pathogens to dampen down overactive immune system
− May be a simplified view of the relationship of pathogens and disorders
− Old hypothesis may not be correct
o Reasons to believe that viral infections ma
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