The diet gets billed as a miraculously enjoyable diet—eat all the fat you want, just cut out the carbs. But the ketogenic diet (also called keto) was never supposed to be fun. It was supposed to treat severe epilepsy. And as a medical treatment, it was only intended to be administered under the supervision of trained nutritionists and physicians. The professionals would be able to monitor patients for potential problems and ensure that their diet was actually keeping them in ketosis—a metabolic state where your body switches from using glucose as energy to using ketone bodies, which come from body fat. They needed those checkpoints because staying in true ketosis is exceptionally challenging for adults.
Another mechanism that could be involved in food-regulation during KD is the gamma aminobutyric acid (GABA) and glutamate regulation. Wu et al. demonstrated that GABAergic signaling from the NPY/AgRP neurons to the parabrachial nucleus (located in the dorsolateral part of the pons) is involved in many regulatory sensory stimuli including taste and gastric distension, regulate feeding behavior. GABA signaling seems to prevent animals from anorexia when AgRP neurons were destroyed (Wu et al., 2009). These findings are yet another contradictory aspect of KDs and food behavior; ketosis should increase the availability of glutamate (via diminution of transamination of glutamate to aspartate) and therefore increase GABA and glutamine levels; moreover, in ketosis, the brain imports a huge amount of acetate and converts it through glia into glutamine (an important precursor of GABA) (Yudkoff et al., 2008). The result of these mechanisms, together with the increased mitochondrial metabolism and flux through the TCA cycle, is an increased synthesis of glutamine and a “buffering” of glutamate. These results are not consistent with the well-documented anorexigenic effect of KDs, and therefore the GABA hypothesis cannot be taken into account despite the mild euphoria often reported during a KD that is probably due to the action of BHB (Brown, 2007) and can help to reduce appetite.
Glucose-sensitive neurons have been identified in a number of CNS regions including the metabolic control centers of the hypothalamus. Medeiros et. al. have used patch-clamp electrophysiology to examine whether neurons in a specific specialized region known as the subfornical organ (SFO), an area where the blood-brain barrier is not present, are also glucose sensitive or not. These experiments demonstrated that SFO neurons are glucose-responsive and that SFO is an important sensor and integrative center of circulating signals of energy status (Medeiros et al., 2012).

Scheme of orexigenic and anorexigenic effects of ketosis. The picture is highly schematic. For more details please see the text. AMPK, AMP-activated protein kinase; CCK, cholecystokinin; GABA, gamma-aminobutyric acid; BHB, β-hydroxybutyric acid; FFA, free fatty acids; ROS, reactive oxygen species; NPY, neuropeptide Y; AgRP, agouti gene-related protein.

The discovery of many appetite-related hormones provided molecular basis for appetite control, decreasing the relevance of the metabolites hypothesis (Karatsoreos et al., 2013). Recently, Sumithran et al. demonstrated that there is a long-term persistence of changes in some peripheral hormones involved in food control (Sumithran et al., 2011). In this study, they found a significant difference in mean levels of many food intake-related hormones 1 year after the cessation of weight loss via the hypocaloric diet. There was a long lasting decrease of anorexigenic compounds: leptin, PYY, cholecystokinin, insulin, and pancreatic peptide and an increase of the orexigenic molecule ghrelin. Moreover, they found that hunger remained elevated 1 year after diet cessation. In a successive study the same group investigated hunger-related hormones after 8 weeks of KD, demonstrating that during ketosis the increase of ghrelin (a strong stimulator of appetite) was suppressed (Sumithran et al., 2013). These results are consistent with those of Ratliff et al (Ratliff et al., 2009), who found no significant change in fasting plasma ghrelin after 12 weeks of VLCD.
Before starting, ask yourself what is really realistic for you, Mattinson suggests. Then get your doctor’s okay. You may also work with a local registered dietitian nutritionist to limit potential nutrient deficiencies and talk about vitamin supplementation, as you won’t be eating whole grains, dairy, or fruit, and will eliminate many veggies. “A diet that eliminates entire food groups is a red flag to me. This isn’t something to take lightly or dive into headfirst with no medical supervision,” she says.