One potential causative factor of diet-induced obesity (DIO) is leptin resistance. Leptin is a potent anorexic hormone in most lean animals. However, the effects of leptin are diminished in obese animals, and this refractiveness is known as leptin resistance. Diets high in fat and sucrose lead to leptin resistance and obesity, yet the causative dietary ingredient(s) remain elusive. Our data demonstrate that a low-fat diet with elevated fructose causes leptin resistance, whereas diets without fructose do not. Leptin signals via the signal transducer and activator of transcription protein 3 (STAT3) and the nutrient sensing AMP-activated kinase (AMPK)/acetyl CoA carboxylase (ACC) pathways. Leptin signals through the latter by promoting dephosphorylation of pAMPK/pACC. We demonstrated that fructose prevents leptin-mediated pAMPK/pACC dephosphorylation, leading to leptin resistance. Over-nutrition also leads to leptin resistance. We suggest that diets that lead to over-consumption, exacerbated by fructose, promote inflammation, endoplasmic reticulum (ER) stress, and reactive oxygen species (ROS) and these specifically inhibit leptin-mediated STAT3 phosphorylation (P-STAT3). We postulate that elevated dietary fructose, but not glucose, impairs the leptin- mediated dephosphorylation of pAMPK/pACC in the hypothalamic arcuate nucleus (ARC) and ventral tegmental area (VTA). Additionally, we postulate that fructose, in synergy with over-nutrition, increases inflammation, ER stress, and ROS, thus inhibiting pSTAT3 signaling. Furthermore, disruptions in both pathways are necessary to promote weight gain. We will test these hypotheses in male Sprague Dawley rats by examining the neural regulation of food intake and body weight, whole body energy homeostasis, and brain region-specific leptin signaling. Exp 1 will examine if 2-week dietary fructose inhibits the leptin-mediated dephosphorylation of pAMPK/pACC or impairs the phosphorylation of STAT3 compared with that of dietary glucose or sucrose. Exp 2 will determine if fructose acts directly on central leptin signaling pathways by central infusion of fructose or glucose. Exp 3 examines if disruptions in both the STAT3 and AMPK leptin signaling pathways are critical for the leptin-resistance promoted weight gain by specific inhibition of the individual pathways. In Exp 4, we will examine if over-nutrition plus fructose (vs. glucose) will induce a greater brain inflammation/ER stress/ROS, and consequently, result in more severe inhibition of leptin-mediated P-STAT3 signaling in the ARC and VTA. Exp 5 will examine the individual contribution of inflammation, ER stress or ROS production to fructose/over-nutrition-induced leptin resistance by infusion of respective inhibitors of these stressors. Our approach is unique because we suggest that fructose plus over-nutrition constitute a two-hit model explaining leptin resistance. An understanding of these mechanisms will provide new therapeutic strategies for obesity, including drugs that target inflammation/ER stress/ROS coupled with low fructose diets to resurrect leptin action.
The American population may be particularly vulnerable to dietary obesity due to chronic consumption of high sugar and fat diets, and obesity-related health complications hasten the onset of disability and death. This proposal seeks to examine the role of dietary fructose and fat in the promoting weight gain. In particular, it examines the way fructose and over-consumption prevents the hormone leptin from its normal action, thus promoting weight and fat gain. Our proposed studies will be conducted in Sprague-Dawley rats, a pre-clinical rodent model for diet-induced obesity in humans.
|Bruce, Erin B; Sakarya, Yasemin; Kirichenko, Nataliya et al. (2018) ACE2 activator diminazene aceturate reduces adiposity but preserves lean mass in young and old rats. Exp Gerontol 111:133-140|
|Côté, Isabelle; Green, Sara M; Yarrow, Joshua F et al. (2018) Oestradiol and leptin have separate but additive anorexigenic effects and differentially target fat mass in rats. J Neuroendocrinol 30:e12646|
|Côté, Isabelle; Green, Sara M; Morgan, Drake et al. (2018) Activation of the central melanocortin system in rats persistently reduces body and fat mass independently of caloric reduction. Can J Physiol Pharmacol 96:308-312|
|Côté, I; Green, S M; Toklu, H Z et al. (2017) Differential physiological responses to central leptin overexpression in male and female rats. J Neuroendocrinol 29:|
|Côté, I; Sakarya, Y; Kirichenko, N et al. (2017) Activation of the central melanocortin system chronically reduces body mass without the necessity of long-term caloric restriction. Can J Physiol Pharmacol 95:206-214|
|Toklu, Hale Z; Scarpace, Philip J; Sakarya, Yasemin et al. (2017) Intracerebroventricular tempol administration in older rats reduces oxidative stress in the hypothalamus but does not change STAT3 signalling or SIRT1/AMPK pathway. Appl Physiol Nutr Metab 42:59-67|
|Carter, Christy S; Khamiss, Dallas; Matheny, Michael et al. (2016) Rapamycin Versus Intermittent Feeding: Dissociable Effects on Physiological and Behavioral Outcomes When Initiated Early and Late in Life. J Gerontol A Biol Sci Med Sci 71:866-75|
|Toklu, H Z; Muller-Delp, J; Sakaraya, Y et al. (2016) High dietary fructose does not exacerbate the detrimental consequences of high fat diet on basilar artery function. J Physiol Pharmacol 67:205-16|
|Scarpace, Philip J; Matheny, Michael; Strehler, Kevin Y E et al. (2016) Rapamycin Normalizes Serum Leptin by Alleviating Obesity and Reducing Leptin Synthesis in Aged Rats. J Gerontol A Biol Sci Med Sci 71:891-9|
|Toklu, Hale Z; Bruce, Erin B; Sakarya, Yasemin et al. (2016) Anorexic response to rapamycin does not appear to involve a central mechanism. Clin Exp Pharmacol Physiol 43:802-7|
Showing the most recent 10 out of 15 publications