Safflower (n-6) and flaxseed (n-3) high-fat diets differentially regulate hypothalamic fatty acid profiles, gene expression, and insulin signalling

Prostaglandins Leukot Essent Fatty Acids. 2018 Jan;128:67-73. doi: 10.1016/j.plefa.2017.12.002. Epub 2017 Dec 8.


Polyunsaturated fatty acids (PUFA) have important signalling roles in the hypothalamus, a region of the brain that regulates whole-body energy homeostasis. While evidence suggests that high PUFA intake can impact hypothalamic activity, the underlying molecular mechanisms regulated by essential dietary n-6 and n-3 PUFA (i.e., linoleic acid and α-linolenic acid, respectively) remain poorly described in this brain region. To differentiate the roles of essential dietary PUFA on hypothalamic function, we fed male rats high-fat diets (35% kcal/d) containing either safflower (linoleic acid) or flaxseed (α-linolenic acid) oil for 2 months. Control rats were fed a low-fat (16% kcal/d) diet containing soybean oil. Hypothalamic fatty acids and gene expression were investigated by gas chromatography and microarray, respectively. Safflower-fed rats had higher total n-6 PUFA content due to increases in linoleic acid, arachidonic acid, and osbond acid compared to the other diet groups, while flaxseed-fed rats had higher total n-3 content due to increases in α-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid. Safflower-fed rats showed augmented expression of genes related to hypothalamic insulin signalling compared to controls. This was mirrored by significant increases in phosphorylated AKTthr308 and AKTser473 levels; indicative of increased PI(3)K/AKT pathway activity. These changes were not observed in the hypothalamus of flaxseed-fed rats. Our findings provide new molecular insights into how essential fatty acids influence the hypothalamus and, potentially, whole-body energy homeostasis. This work also provides new knowledge to better understand the impact of essential fatty acids on metabolic and behavioral phenotypes.

Keywords: Alpha-linolenic acid; Gas chromatography; High-fat diet; Hypothalamus; Linoleic acid; Microarray.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diet, High-Fat
  • Fatty Acids / metabolism
  • Fatty Acids, Omega-3 / pharmacology
  • Fatty Acids, Omega-6 / pharmacology
  • Gene Expression Regulation / drug effects*
  • Hypothalamus / drug effects*
  • Hypothalamus / physiology
  • Insulin / metabolism*
  • Linseed Oil / chemistry
  • Linseed Oil / pharmacology*
  • Male
  • Rats, Sprague-Dawley
  • Safflower Oil / chemistry
  • Safflower Oil / pharmacology*


  • Fatty Acids
  • Fatty Acids, Omega-3
  • Fatty Acids, Omega-6
  • Insulin
  • Safflower Oil
  • Linseed Oil