Intestine Specific Ablation of Acyl-CoA Synthetase 5 (ACSL5) Increases Satiety and Protects Against Diet Induced Obesity
Abstract: The intestine
is recognized as an absorptive organ, facilitating the internalization of nutrients from
the diet for use by the body. In addition to this canonical role a growing body of
research has established the intestine as an active regulator of energy homeostasis.
Through multiple signaling mechanisms the intestine is capable of modifying whole body
energy balance in response ... read moreto dietary components such as fatty acids (FA). Altering
normal intestinal FA absorption dysregulates these signaling networks and has the
potential to cause profound physiological changes, including weight loss, improved
insulin sensitivity, improved glucose tolerance, and protection from high fat diet
induced obesity. Despite the influence of the intestine on systemic metabolism, many
intestinal enzymes involved in lipid absorption have poorly defined functions and their
contributions to intestine dependent regulation of whole body energy metabolism are
largely unknown. The initial phase of cellular FA absorption involves the acylation of
FFA to acyl-CoA by the acyl-CoA long chain synthetase (ACSL) class of proteins.
Intestinal acyl-CoA's are the precursors for multiple reactions occurring in intestinal
lipid metabolism including esterification of fat soluble Vitamin A, esterification of
Cholesterol, formation of TAG from FA, and oxidation of FA. ACSL5 is the major ACSL
isoform in the intestine. Whole body knockout of ACSL5 impairs intestinal TAG metabolism
and increases whole body energy metabolism. The underlying molecular mechanisms by which
ACSL5 functions in intestinal lipid handling and regulation of energy expenditure remain
undefined. Thus, the specific aims of this project are (1) to determine the role of
enterocyte ACSL5 in regulating absorption of dietary TAG and cholesterol and (2) to
determine the effects of intestinal ACSL5 on the regulation of energy metabolism. To
determine the role of ACSL5 in lipid absorption and regulation of energy expenditure we
generated a novel, intestine-specific inducible knockout model of ACSL5 (ACSL5IKO). We
found that intestine specific loss of ACSL5 causes delayed gastric emptying and reduced
TAG secretion, but does not cause gross lipid malabsorption. Surprisingly when ACSL5IKO
mice are challenged with a high fat diet (HFD) they experience rapid and sustained
protection from body fat accumulation. We demonstrate that this protection is due
largely to reductions in energy intake caused by increased satiety signaling. Our data
indicate multiple potential mechanisms by which intestine-specific loss of ACSL5 may
alter satiety signaling including an altered bile acid pool composition, increased
release of enteroendocrine hormones, and increased activation of intestinal peroxisome
proliferator activated receptor alpha (PPARα). Importantly, the observed
protection from diet induced obesity in the absence of fecal fat loss implicates
intestinal ACSL5 as a potential therapeutic target for the treatment of obesity and
related metabolic complications.
Thesis (Ph.D.)--Tufts University, 2018.
Submitted to the Dept. of Biochemical and Molecular Nutrition.
Advisor: Andrew Greenberg.
Committee: Joel Mason, Edward Saltzman, and David Cohen.
Keywords: Nutrition, and Biology.read less