title: From chronic overnutrition to insulin resistance: the role of fat-storing capacity and inflammation.
abstract: OBJECTIVE
  We analyze how the inflammatory state in adipose tissue caused by a condition of chronically positive energy balance can lead to insulin resistance first in adipose tissue, then in all insulin-sensitive tissues.
  
  
  RESULTS
  Chronic nutrient overload causes an increase in adipose depots that, if adipose tissue expandability is low, are characterized by an increased presence of hypertrophic adipocytes. This adipocyte hypertrophy is a possible stress condition for the endoplasmic reticulum (ER) that would lead to a proinflammatory state in adipose tissue. In this condition, ER stress would activate metabolic pathways that trigger insulin resistance, release of macrophage chemoattractant proteins, and in chronic inflammation, the death of the hypertrophic adipocyte. The infiltrated macrophages in turn release inflammatory proteins causing further recruitment of macrophages to adipose tissue and the release of inflammatory cytokines. Following these events, insulin resistance becomes extended to all adipose tissue. Insulin-resistant adipocytes, characterized by low liposynthetic capacity and high lipolytic capacity, cause increased release of free fatty acids (FFA). FFA released by lipolitic adipocytes may also activate Toll-like receptors 4 and then chemokines and cytokines release amplifying insulin resistance, lipolysis and inflammation in all adipose tissue. Moreover, increased circulating FFA levels, reduced circulating adiponectin levels and leptin resistance lead to decreased lipid oxidation in non-adipose tissues, thereby triggering ectopic accumulation of lipids, lipotoxicity and insulin resistance.
  
  
  CONCLUSIONS
  All the conditions that increase circulating fatty acids and cause lipid overloading (obesity, lipoatrophy, lipodystrophy, catabolic states, etc.) induce a lipotoxic state in non-adipose tissues that gives rise to insulin resistance.
authors.affiliation: Department of Biological Sciences, Section of Physiology, University of Naples Federico II, Via Mezzocannone 8, 80134 Naples, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Lionetti
authors.forename: M P
authors.initials: MP
authors.lastname: Mollica
authors.forename: A
authors.initials: A
authors.lastname: Lombardi
authors.forename: G
authors.initials: G
authors.lastname: Cavaliere
authors.forename: G
authors.initials: G
authors.lastname: Gifuni
authors.forename: A
authors.initials: A
authors.lastname: Barletta
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D050154:Adiposity; D000818:Animals; D002908:Chronic Disease; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D006984:Hypertrophy; D007249:Inflammation / Q000209:etiology* / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism*; D007333:Insulin Resistance; D044343:Overnutrition / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D015398:Signal Transduction; D013312:Stress, Physiological
chemical_list: D005227:Fatty Acids; D018836:Inflammation Mediators