Sunday, April 1, 2012

Leptin Resistance

Hormone resistance can occur when the number of functional receptors is decreased or when the hormone has decreased signal transduction.  Suppressor of cytokine signalling 3 (SOCS3) and protein-tyrosine phosphatase 1B (PTP1B) inhibit the signal transduction of leptin, causing leptin resistance [1] [2] [3] [4] [5].  The next question becomes: what increases SOCS3 and PTP1B, and decreases the number of functional receptors? 


Lipopolysaccharide is an endotoxin of gram-negative bacteria, is highly inflammatory and potently induces SOCS3 expression by elevating pro-inflammatory cytokines such as IL-6 [7] [8].  The body is mostly shielded from LPS by the intestinal barrier, but more of it can enter the blood stream if bacteria overpopulate the small intestine (small intestinal bacterial overgrowth), if immune system is weak or if there is intestinal permeability [9]. 

Evidence to support the role of LPS and SOCS3 in LR and obesity: 

  • DIO results in altered gut bacteria and intestinal permeability [10]
  • Mice without enzymes that detoxify LPS are more vulnerable to weight gain [10]
  • Mice lacking TLR4, which detects LPS and induces inflammation, were resistant to weight gain in DIO [10]
  • Germ free mice eat less and have a lower metabolic rate, but are overall resistant to DIO [10]
  • LPS infusion has a similar effect as DIO [10]
  • LPS is 2.7 times higher in DIO (but 10-50 times lower than sepsis) [11]
  • Mice without the SOCS3 gene are resistant to DIO [12]

Small intestine bacterial overgrowth (SIBO) can the result of consuming a significant amount of indigestible carbohydrates that can be rapidly fermented by bacteria.  These carbohydrates are known as FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols).  The polyols are the sugar alcohols, which are used as non-caloric sweeteners and smaller amounts are found in some fruits, particularly stone fruits and pears.  The monosaccharides and disaccharides refer to fructose/sucrose, found in fruits and added sugar, with fructose malabsorption* and galactose/lactose, found in milk, with lactose intolerance**.  The oligosaccharides refer to fructans, found mostly in wheat and also in some vegetables like onions, and galactans, found in legumes.  Both fructans and galactans are poorly absorbed.  Soluble fibre is fermentable, but doesn’t have the SIBO effect because the fermentation is much slower [13] [14] [15]. 

Several nutrients are need for proper immune function such as iron, zinc, copper and selenium and vitamins A, B6, B9, B12, C, D and E.  Inadequate intake of these nutrients could suppress immunity [16] [17].  Chronic inflammation [18], stress and drugs like cortisone suppress immune activity [9] 

Things that can increase intestinal permeability include: gluten [19], ethanol [20], a high intake of fructans [21], pro-inflammatory cytokines, glucocorticoids, oxidative stress, NSAIDs, psychological stress and acute infections [22] [23] 

* Fructose malabsorption is dose and concentration dependent.  The rate of fructose malabsorption at 25g is 40% and at 50g is 60-70%.  The rate of sorbitol malabsorption at 10g is 100% [24].  In studies where fructose is providing ~60% of the total calories are the researchers measuring the metabolic effects or digestive/microbiota effects of high fructose? 

** Most people of middle/northern European descent aren’t lactose intolerant, but most people of southern European/Asian/African descent are lactose intolerant [24] 


Many reviews on leptin resistance mention endoplasmic reticulum stress (ER stress) as something that also causes LR.  This is because ER stress increases the expression of PTP1B [25], and PTP1B has the effect on leptin resistance.  Mitochondrial dysfunction (MD) is strongly associated with and often leads to ER stress because the ER has a high need for ATP and because elevated ROS from the causes and effects of MD can lead to oxidative stress in the ER [26] [27]. 

More evidence to support the role of MD, ER stress and PTP1B in LR and obesity:

  • Mice without the PTP1B gene are resistant to DIO [6]
  • ER stress inhibitors restore leptin sensitivity in DIO and lower food intake and body weight of obese mice [2]
  • ER stress is increased in other tissues in leptin resistance and obesity [3]
  • People with obesity tend to have lower numbers of mitochondria and a slower, less efficient electron transport chain [28] 

See my post mitochondrial dysfunction on how it can be caused, other downstream effects and how to support mitochondrial function.

Also, oxidative stress from the causes and effects of mitochondrial dysfunction is another source of chronic inflammation and elevates pro-inflammatory cytokines [29], which may increase SOCS3 and leptin resistance. 


DIO quickly elevates pro-inflammatory cytokines, such as IL-1, IL-6 and TNF-α, and IgG in the arcuate nucleus of the hypothalamus, but not the liver or adipocytes, before weight gain [30] [31].  TNF-α can signal apoptosis in the hypothalamus and DIO increases apoptosis of hypothalamic neurons [32].  Overtime the number of leptin receptors decrease leading to less leptin signalling and leptin resistance. 

Inflammation and MD/ER stress are the main promoters of apoptosis, so this doesn’t change the overall direction.  But this supports the idea of obesity being a chronic disease and can explain why formerly obese people struggle with weight loss even when they are doing everything right.  Reducing the SOCS3 and PTP1B signal is likely much easier than growing and integrating new neurons (neurogenesis) 

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