Insulin resistance and weight gain: chicken or egg?

By Tamzyn Murphy, RD, MSc (Dist.)


Does insulin cause obesity or does obesity cause insulin resistance? 

Insulin promotes fat storage

We know that insulin promotes fat storage: “Insulin is a critical regulator of virtually all aspects of adipocyte biology, and adipocytes are one of the most highly insulin-responsive cell types.” (Kahn BB & Flier JS, 2000). Insulin does this by… 

  1. promoting glucose transport into the adipocyte (fat cell)
  2. promoting fat storage (lipogenesis) 
  3. inhibiting fat breakdown (lipolysis)
  4. promoting fat uptake from circulating lipoproteins into fat (adipose) storage (by stimulating lipoprotein lipase in adipose tissue)
  5. promoting fat cell (adipocyte) differentiation and maturation


Insulin resistance also promotes fat storage 

-though at first glance the contrary appears to be true

So, this begs the question, when insulin resistance develops (cells become resistant to insulin’s effect), surely adipocytes become resistant to insulin’s effects too, and as such you’d expect to see reduced fat storage resulting from reduced insulin signalling? We know this isn’t the case though. Insulin resistance often goes hand in hand with weight gain, rather than loss. The reasons for this may be that:

  1. Adipose (fat) tissue is more insulin sensitive than muscle (Kahn BB & Flier JS, 2000)
  2. Insulin signals different cell pathways (Kahn BB & Flier JS, 2000, Figure 1). And cells’ pathways don’t all become similarly insulin resistant (Kahn BB & Flier JS, 2000). Insulin’s glucose uptake signalling pathway may be impaired, while the lipogenesis (fat forming) and anti-lipolytic (anti-fat-breaking-down) pathways may still be sensitive, allowing fat to expand (Kahn BB & Flier JS, 2000).  

Insulin concentrations increase under insulin resistant conditions, to overcome the resistance and “force” glucose out of the blood into the cells, thereby preventing hyperglycaemia (high blood ‘sugar’ levels). The increased circulating insulin continues to act on the insulin sensitive adipocytes and the pathways involved in fat formation to promote fat/weight gain and obesity. So, insulin resistance promotes obesity.


Fat storage or adiposity promotes insulin resistance

Conversely, fat storage or adiposity (particularly in the belly or centrally) also promotes insulin resistance. This may be due to:

  1. Lipolytic (fat-break-down) activity of central adipose tissue – increasing free fatty acid levels and flux in circulation and cells. Fatty acid build-up in cells interferes with insulin signalling (by creating lipotoxic intermediates) thereby promoting insulin resistance (Montgomery, 2015).
  2. Adipose’s endocrine (hormone) effects (cortisol, oestrogen, leptin).


So, it appears that it really is a chicken and egg situation… insulin resistance promotes obesity (via hyperinsulinemia or high insulin concentrations) and visa versa, in a vicious cycle of ill health. 


Stop the vicious cycle

How does one stop the ‘Lifecyle’ then (or should we call it ‘Death-cycle’)? Start by either 1.) losing the fat OR 2.) dropping the insulin, and the other should follow. Or simply target both by reducing dietary carbohydrate, which 1.) reduces hunger thereby promoting spontaneous calorie reduction and weight loss, AND 2.) reduces circulating insulin concentrations as less is needed when less dietary glucose is entering circulation (Ludwig et al., 2018). Simple.


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