Sensitivity to the Anorectic Effects of Leptin Is Retained in Rats Maintained on a Ketogenic Diet despite Increased Adiposity

Abstract

Background: Rats maintained on a ketogenic diet (KD; 80% fat, 15% protein, 5% carbohydrate) have increased adiposity and leptin as compared to chow-fed controls (CH; 16% fat, 19% protein, 65% carbohydrate), although body weights and daily caloric intakes do not differ. Methods: Rats maintained on a KD or CH were assessed for responsivity to intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) leptin. Hypothalamic gene expression was evaluated to determine the effects of KD on proopiomelanocortin (POMC) mRNA expression and components of the leptin-signaling system. Results: Caloric intake by KD rats was decreased at a lower dose of i.p. leptin (100 µg) than was required to reduce intake by CH rats (leptin, caloric intake was reduced in KD rats as compared to intake following i.p. saline; p < 0.05). In a separate experiment to evaluate responsivity to i.c.v. leptin, the minimal dose of leptin required to significantly reduce 24-hour caloric intake did not differ between the groups. In the arcuate nucleus, POMC mRNA was elevated after a lower dose of i.c.v. leptin in KD rats (5 µg) than was required to increase POMC mRNA expression in CH rats (15 µg) or reduce caloric intake in either group. Finally, evaluation of the level of phosphorylated STAT3 (pSTAT3) in the arcuate and SOCS3 mRNA in the hypothalamus revealed significantly more pSTAT3-positive cells and increased SOCS3 mRNA expression at baseline for KD rats, compared to CH, neither of which was further increased following i.p. leptin administration. Conclusion: These data demonstrate that despite increased adiposity, leptin and markers of leptin resistance, responsivity to the anorectic effects of exogenous leptin is retainable during maintenance on a KD.

Hypothalamic hormones and metabolism

“…An expected consequence of the increase in fat mass is an increase in leptin because leptin levels are proportional to fat mass (Maffei et al, 1995). Several studies confirm this prediction by showing that the ketogenic diet may more than double serum leptin levels (Kinzig et al, 2005; Thio et al, 2006; Honors et al, 2009; Kinzig and Taylor, 2009; Kinzig et al, 2010), though some find no change (Kennedy et al, 2007). …”

“…It also does not modify AgRP gene expression in the hypothalamus (Kennedy et al, 2007). Surprisingly, the diet decreases POMC expression in the hypothalamus even though leptin should increase its expression (Kennedy et al, 2007; Kinzig and Taylor, 2009; Kinzig et al, 2010). This area deserves further study because the results likely will lead to a better understanding of the neurohormonal effects of ketogenic diet and the neuronal network involved in regulating energy homeostasis.…”

“…Some of the expected metabolic changes in serum include increased ketones and an altered lipid profile. Though studies typically report increases in ketones ranging from 2-10 fold, not all studies report increased total cholesterol, low-density lipoprotein cholesterol, and triglycerides (Uhlemann and Neims, 1972; Schwartz et al, 1989; Bough and Eagles, 1999; Dell et al, 2001; Liu et al, 2003; Kwiterovich et al, 2003; Fraser et al, 2003; Nylen et al, 2005; Thio et al, 2006; Samala et al, 2008; Raffo et al, 2008; Spulber et al, 2009; Kinzig and Taylor, 2009; Badman et al, 2009; Hansen et al, 2009; Thio et al, 2010; Kinzig et al, 2010). …”

“…In rodents, the ketogenic diet can double fat mass as a percentage of total body mass (Thio et al, 2006; Ribeiro et al, 2008; Honors et al, 2009; Kinzig and Taylor, 2009; Kinzig et al, 2010) (Fig. 1).…”

“…For example, conditions associated with weight loss such as fasting cause both to decrease whereas high energy states associated with weight gain, such as overeating, cause both to increase (Schwartz et al, 2003; Woods and D'Alessio, 2008). Thus, the ketogenic diet induces a unique metabolic state (Kennedy et al, 2007), and the opposing changes in leptin and insulin levels produce a unique neurohormonal state (Honors et al, 2009; Kinzig et al, 2010). …”