The Gut-brain Axis: a Novel Target for Treating Behavioral Alterations in Obesity

In prior studies we have demonstrated an inverse relationship between body mass index and
response in the dorsal striatum (DS) during consumption of a palatable milkshake (Stice et
al. 2008). We have also shown that the magnitude of the reduced response predicts weight
gain, especially in individuals who carry a copy of the A1 allele of the taq1A polymorphism
(Stice et al. 2008). Since the A1 allele is associated with reduced striatal D2 receptors
(Jonsson et al. 1999, Noble 2003, Noble et al. 1991, Pohjalainen et al. 1998, Ritchie et al.
1998, Thompson et al. 1997), this finding implicates the dopamine system in the reduced blood
oxygen level dependent (BOLD) response. Our results also indicate that this reduced response
is a consequence, rather than a cause of obesity, since gaining weight (Stice et al. 2010),
but not risk for obesity (Stice et al. 2011) (by virtue of parental obesity), is associated
with reduced DS response to palatable food. Taken together the results indicate that
increased adiposity is associated with blunted DS response to palatable food that may reflect
altered dopamine signaling. More recently we determined that reduced DS responses in
overweight and obese subjects are associated with increased impulsivity measured with the
Barratt Impulsiveness Scale and a go no/no-go task (Babbs et al, In Press).

Related to these findings in humans, preliminary work in rodents shows that exogenous
administration of N-Acylethanolamines, such as oleoylethanolamine (OEA) can normalize
high-fat diet induced dopamine decreases in DS and possibly induce a shift in preference
(Tellez et al., In Press). Human testing of OEA supplementation is possible based on the
availability of a dietary supplement containing the OEA precursor NOPE-EGCG ((PhosphoLEANtm,
100 mg NOPE+50mg EGCG per capsule). PhosphoLEAN has been shown to enhance adherence to
dietary advice in overweight healthy subjects (Rondanelli et al. 2009, Mangine et al. 2012).

We therefore propose a double-blind cross-over study to test whether PhosphoLean will rescue
striatal function, increase adherence to a diet, reduce weight-gain after a diet, improve
performance on impulsivity, go/no-go tasks, and negative outcome learning, and shift fat and
sweet preference in overweight/obese human subjects.

Inclusion Criteria:

Right handed, English speaking, be a non-smoker (never smoked more than 2 cigarettes per
month). Subjects will have a Body Mass Index > 25 kg/m2 (overweight/obese). Subjects are in
good health. Subjects are able to provide a letter from their physician stating that they
have had a physical exam in the past year and are in general good health and have
specifically tested in the normal range for thyroid function and Hemoglobin 1Ac (and as
such do not suffer from common metabolic disorders). In addition to this we will at intake
confirm normal blood pressure, blood sugar and electrolyte balance for every subject.

Exclusion Criteria:

a) serious or unstable medical illness (e.g., cancer); b) past or current history of
alcoholism or consistent drug use; c) current and history of major psychiatric illness as
defined by the Diagnostic and Statistical Manual Diploma in Social Medicine-IV criteria
including eating disorders, d) medications that affect alertness (e.g., barbiturates,
benzodiazepines, chloral hydrate, haloperidol, lithium, carbamazepine, phenytoin, etc.)and
any psychoactive drugs or anti-obesity agents; e) history of major head trauma with loss of
consciousness; f) ongoing pregnancy; g) known taste or smell dysfunction; h) a diagnosis of
diabetes; i) any known food allergy, certain food sensitivities (lactose); j) pregnant or
nursing women, k) history of metalworking, injury with shrapnel or metal slivers, and major
surgery; l) history of pacemaker or neurostimulator implantation.