Decreased, Ketogenesis (production of ketone bodies) leads to Not Increased, Circulating Ketone Bodies

The KE, “ketogenesis (production of ketone bodies)” is critical to supporting general systemic energy homeostasis in fasting events (Cahill 2006, Evans et al 2004, Sengupta et al 2010).  Interference with ketogenesis, for example by PPARα inhibition, has been demonstrated to inhibit β-hydroxybutyrate production (measured in serum) during fasting events in mice (Badman et al 2007, Potthoff 2009, Sengupta et al 2010).  The Badman et al (2007) study indicated that metabolism of fatty acid substrates (measured as liver triglycerides) that would otherwise contribute to β-hydroxybutyrate production was additionally inhibited under PPARα knockout.  

In a fasting state, humans transition from the use of exogenous glucose to glucose derived from glycogen within 4 hours with a steadily increasing proportion of glucose usage that is derived from gluconeogenesis up to 2 days (Cahill 2006).  Beyond 2 days of fasting, ketone body production (β-hydroxybutyrate) increasingly supports the energy demands of the brain (Cahill 2006).

Physiological studies of the progression of human starvation have identified that the preferred metabolic fuel is glucose in the fed state and progressing through two days of fasting, afterward ketone bodies become increasingly important for meeting energy demands (Cahill 2006, Owen et al 2005).  Substrates derived from carbohydrates, fats and protein can contribute to gluconeogenesis (Cahill 2006, Gerich et al 2001) whereas substrates derived from fatty acids are the primary contributors to ketogenesis (Desvergne and Wahli 1999).  Mobilization of fatty acids as a metabolic fuel source increase dramatically during fasting to support both gluconeogenesis and ketogenesis (Evans et al 2004).   Cahill (2006) and colleagues have demonstrated the importance of ketone body production, especially β-hydroxybutyrate, for maintaining energy homeostasis during starvation.  β-hydroxybutyrate serves as an alternative substrate to glucose for providing energy to the brain in the starvation state, providing ATP at higher efficiency relative to the glucose substrate (Cahill 2006).  Interference with ketogenesis, for example by PPARα inhibition, has been demonstrated to inhibit β-hydroxybutyrate production (measured in serum) during fasting events in mice (Badman et al 2007, Potthoff 2009, Sengupta et al 2010)  and cause hypoketonemia (Muoio et al 2002).  The Badman et al (2007) study indicated that metabolism of fatty acid substrates (measured as liver triglycerides) that would otherwise contribute to β-hydroxybutyrate production was inhibited under PPARα knockout.   Increased concentrations of circulating ketone bodies is indicative of potential metabolic fuel deficits in fasting animals (Cahill 2006), and a lack of increase in circulating ketone bodies during fasting, especially in conjunction with elevated blood triglycerides, indicates impaired ketogenesis and potentially impaired bioenergetic potential.

A potential implication of decreased ketone body production is stress on cardiac function given that energy-stressed heart tissue shifts reliance away from fatty acids toward ketone bodies (β-hydroxybutyrate) to fuel production of the ATP needed to maintain the heart’s mechanical function (Aubert et al 2016).  Related to this observation, PPARα-knockout mice reached exhaustion sooner than wild types in an exercise challenge which corresponded with significantly decreased β-hydroxybutyrate in serum indicating hypoketonemia in PPARα-knockout mice versus wild types (Muoio et al 2002).  Overall, diminished PPARα function, especially in combination with fasting /diminished nutrition and/or excessive exercise may contribute to impaired maintenance on systemic energy budget.

Availability of alternative energy substrates may chance the dynamics of this KER.

Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?

The results presented in the references cited above provide many of the quantitative relationships among KEs.  Multiple signaling pathways are involved in the starvation response, so additional response-response relationships are likely to play a role in the systemic response as well as interaction with the KE, “decreased ketogenesis (production of ketone bodies)” and the KE, “no increase of circulating ketone bodies”.  We are not currently aware of any models available to extrapolate results among KEs.

The relationships described herein have been primarily established in human and rodent models.