The Trajectory from Mood to Obesity

Purpose of Review To describe and explain the relationships between mood disturbances and the development of obesity. Recent Findings That depression, anxiety, PTSD, or severe stresses can promote obesity as a side-effect of the drugs used to treat them, or through “carbohydrate craving” to enhance brain serotonin synthesis and alleviate dysphoria by consuming foods that are rich in both carbohydrates and fats. That seasonal affective disorder and severe PMS can independently cause patients to overconsume foods rich in both carbohydrates and fats. Summary The obesity caused by drugs or mood disorders associated with “carbohydrate craving” leading to excess calorie intake can be suppressed by dietary measures. Keywords: Depression; Anxiety; Obesity; PTSD; Serotonin; Weight gain; Dietary carbohydrate

A Nutrient Combination that Can Affect Synapse Formation

Brain neurons form synapses throughout the life span. This process is initiated by neuronal depolarization, however the numbers of synapses thus formed depend on brain levels of three key nutrients—uridine, the omega-3 fatty acid DHA, and choline. Given together, these nutrients accelerate formation of synaptic membrane, the major component of synapses. In infants, when synaptogenesis is maximal, relatively large amounts of all three nutrients are provided in bioavailable forms (e.g., uridine in the UMP of mothers’ milk and infant formulas). However, in adults the uridine in foods, mostly present at RNA, is not bioavailable, and no food has ever been compelling demonstrated to elevate plasma uridine levels. Moreover, the quantities of DHA and choline in regular foods can be insufficient for raising their blood levels enough to promote optimal synaptogenesis. In Alzheimer’s disease (AD) the need for extra quantities of the three nutrients is enhanced, both because their basal plasma levels may be subnormal (reflecting impaired hepatic synthesis), and because especially high brain levels are needed for correcting the disease-related deficiencies in synaptic membrane and synapses.National Institutes of Health (U.S.

Enhancing Synaptogenesis in Diseases Characterized by Deficiencies in Brain Synapses

The loss of hippocampal and cortical synapses, resulting from impaired synaptogenesis, accelerated synaptic degeneration, or both, is one of the earliest neuropathologic findings in Alzheimer’s Disease and is the finding that best correlates with cognitive symptoms (DeKosky and Scheff, 1990; Terry et al., 1991; Selkoe, 2002). A similar decrease in brain synapses is an early finding in an animal model of AD which overproduces A-beta peptides (Jacobsen et al., 2006), and aggregates of such peptides, applied locally to the brain, can also damage synapses, distort neurites, and decrease the numbers of the dendritic spines which are essential precursors for glutamatergic synapses (Jacobsen et al., 2006; Spires-Jones et al., 2007; Knobloch and Mansuy, 2008). These observations have supported the widely-held view that a treatment that would block the synthesis of A-beta or remove it from the circulation, might – by depleting its levels in brain – slow the loss of synapses in AD and thereby sustain cognitive functions in patients. A generation of creative and diligent researchers has provided us with abundant information about A-beta’s synthesis, fates, and toxic effects, and this information has been used to generate rationally-designed drug candidates for treating the disease. However to date none of these candidates – even ones shown to reduce brain levels of A-beta oligomers and senile plaques – has been successful in sustaining cognition

Strategies for enhancing catecholamine-mediated neurotransmission

Major findings made during this project period included the following observations: changes in tyrosine availability do affect brain dopamine release, as assessed by in vivo microdialysis, but that neuronal feedback mechanisms limit the durations of this effect except when dopaminergic neurotransmission has been deficient; the circulating hormone TRH markedly stimulates brain dopamine release, an effect probably mediated by its diketopiperazine metabolite; the amount of circulating L-dopa which enters the brain is both enhanced by carbohydrate consumption and suppressed by protein intake (both nutritional effects can be damaging, inasmuch as a sudden rush of L-dopa into the brain can facilitate dyskinesias, while the inhibition of brain L-dopa uptake by proteins suppresses its conversion to brain dopamine; an appropriate mixture of dietary proteins and carbohydrates can obviate both effects); serotonin release from superfused hypothalamic slices is a linear function of available tryptophan levels throughout the normal dynamic range; the daily rhythm in plasma melatonin levels is abnormal both in the sudden infant death syndrome and in women with secondary amenorrhea; tyrosine can potentiate the anorectic effects of widely-used sympathomimetic drugs; newly-described COMT inhibitors can enhance brain dopamine release in vivo; and a cell culture system, based on Y-79 (retinoblast) cells, exists in which melatonin reliably suppresses dopamine release

Increased adrenal secretion of norepinephrine and epinephrine after endotoxin and its reversal with corticosteroids

Two groups of dogs were subjected to an LD60 of E. coli endotoxin. Group II animals were pretreated with 30 mg/kg of methyl prednisolone sodium succinate before the intravenous endotoxin. All animals had hypotension and diminished cardiac index after endotoxin administration.The nonsteroid dogs, Group I, demonstrated increased adrenal secretion of norepinephrine and epinephrine. Arterial plasma catecholamines were comparable. Group II steroid-treated animals demonstrated lower adrenal secretion of norepinephrine and epinephrine when compared to Group I, nonsteroid animals. These results demonstrate that pretreatment with pharmacologic doses of synthetic corticosteroids exerts a specific effect on the adrenal medulla in endotoxin shock that profoundly limits adrenal catecholamine release.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/22090/1/0000514.pd

Carbohydrate craving in obese people: Suppression by treatments affecting serotoninergic transmission

We examined the existence of carbohydrate cravings, and the effects on such cravings of treatments that enhance serotonin release, among 24 obese subjects who claimed to have excessive appetites for carbohydrates. Subjects living in a college dormitory for four weeks were given three fixed meals daily and allowed to choose at will among five protein‐rich or five carbohydrate‐rich isocaloric snack foods, provided via a vending machine. For two weeks, they received no treatment (study 1) or a placebo (study 2); for the next two weeks, they received placebo, d‐1 fenfluramine or 1‐tryptophan. All but one of the subjects exhibited a marked preference for carbohydrate‐rich over protein‐rich snacks during the first two weeks of the study. The average daily intake of carbohydrate‐rich snacks was 4.1 ± 0.4 and of protein‐rich snacks 0.8 ± 0.3. Seventeen of the subjects failed to consume any protein snacks on most days during the baseline or test periods, thus it was not possible for us to examine the effect of test treatments on protein snack intake. Fenfluramine administration significantly reduced carbohydrate snacking in six of nine test subjects, as well as in the group as a whole (2.4 ± 0.6 snacks/day vs 4.2 ± 0.6 during the two‐week baseline period). Tryptophan significantly diminished carbohydrate intake in three of the eight treated subjects, and increased it in one subject; it did not significantly modify snacking patterns in the group as a whole. Placebo administration did not affect carbohydrate intake in any of the seven test subjects. These observations show that some obese people do consume carbohydrate‐rich snacks frequently and preferentially, and that this behavior can sometimes be diminished by treatments thought to enhance serotonin's release (fenfluramine) or synthesis (tryptophan)

Inhibition of Neuraminidase Inhibitor-Resistant Influenza Virus by DAS181, a Novel Sialidase Fusion Protein

Antiviral drug resistance for influenza therapies remains a concern due to the high prevalence of H1N1 2009 seasonal influenza isolates which display H274Y associated oseltamivir-resistance. Furthermore, the emergence of novel H1N1 raises the potential that additional reassortments can occur, resulting in drug resistant virus. Thus, additional antiviral approaches are urgently needed. DAS181 (Fludase®), a sialidase fusion protein, has been shown to have inhibitory activity against a large number of seasonal influenza strains and a highly pathogenic avian influenza (HPAI) strain (H5N1). Here, we examine the in vitro activity of DAS181 against a panel of 2009 oseltamivir-resistant seasonal H1N1 clinical isolates. The activity of DAS181 against nine 2009, two 2007, and two 2004 clinical isolates of seasonal IFV H1N1 was examined using plaque number reduction assay on MDCK cells. DAS181 strongly inhibited all tested isolates. EC50 values remained constant against isolates from 2004, 2007, and 2009, suggesting that there was no change in DAS181 sensitivity over time. As expected, all 2007 and 2009 isolates were resistant to oseltamivir, consistent with the identification of the H274Y mutation in the NA gene of all these isolates. Interestingly, several of the 2007 and 2009 isolates also exhibited reduced sensitivity to zanamivir, and accompanying HA mutations near the sialic acid binding site were observed. DAS181 inhibits IFV that is resistant to NAIs. Thus, DAS181 may offer an alternative therapeutic option for seasonal or pandemic IFVs that become resistant to currently available antiviral drugs