best, me: Remembering Tim Bartness

Timothy J. Bartness died on September 24, this year (2015), and the progress of research on obesity will halt in its tracks, or so I feared until I started reading what his students are posting.

If you didn’t have the good fortune to know him, Tim Bartness was brilliant, hilarious, and intense. He did innovative work on many frontiers. He elucidated how day length controls body fat loss and gain. He showed how chemical messengers in the brain affect hunger. When he studied food intake, he didn’t limit his observations to eating. He also studied food hoarding, or as he called it, “shopping for food.” Tim was on the verge of understanding how adipose tissue talks and listens to the brain.

If you didn’t know that your fat sends and receives neural input and output, then you weren’t up-to-date on the frontiers of obesity research. Tim had recently been appointed to head an obesity institute at Georgia State University. In his short life, he published more than 200 papers that received almost 10,000 citations, and almost 4,000 of these citations occurred since 2010. He had an important impact on his field of research, and had he chosen to study rats or mice instead of hamsters, more of my fellow neuroendocrinologists would recognize and make use of his foundational, inspired research. He would have loved that I said that.

Moreover, Tim Bartness was my science big brother– not the Orwellian big brother-is-watching-you kind, but the “I’ve-always-got-your-back-but-you’ll-never-be-as-great-as-I-am” kind of older sibling. Tim and I shared two of the same academic parents and grandparents (George Wade and Irv Zucker) (Tim’s full academic lineage appears on Neurotree), and so Tim and I learned, lived by, and then handed down the same set of advice, tricks, and scientific standards. Our loyalty to each other was not nepotistic, but based on our shared ideas about what constitutes hard evidence. We were writing a “how-to” manual for survival in our crazy academic science jobs.

I’ve lost a big brother, and the weight of this emptiness has left me weirdly paralyzed with confusion, heart-broken, and deeply sad. It feels almost wrong to think there might be something to be gained.

Of course we have gained from his life, and thanks to the internet, much of what we have gained is all around me and right in my face…in my Facebook to be more exact. On Facebook, I see not only his picture but hear Tim’s voice.

Tim’s voice is clearly living and breathing in the minds of his students and colleagues. What’s more, these voices are versions of George’s and Irv’s teachings, living on, even in these ridiculously young students.

Here are just a small sampling of quotes from Tim’s students and colleagues:

Laura Been: … We are all better scientists (and better people) for having Tim as a mentor and a friend. I can’t write anything without hearing his voice in my head (While vs. Whereas; Since vs. Because; never starting a sentence with an adverb). He will be very missed!!

Nicole Victoria: I refer to a Tim Bartness teaching almost on a daily basis and have passed them on to grad students, post-docs, my post-doc advisor and other colleagues (e.g. Presentations: Question, picture, answer. Only use ‘Since’ when referring to time. Hypotheses are present tense statements that answer your experimental question, whereas predictions are future tense statements using ‘if, then’. Use ‘In addition’ and never ‘Additionally’ to start a sentence…). I started talking about Strong Inference and alternative hypothesis testing at a job interview with the FDA the other day. They loved it; I thought of Tim and sent him a mental thank you. He had a dramatic impact on the GSU biology, psychology and neuroscience groups. Clearly he is going to live on in us all and our interactions with others. So sad to hear that Tim has passed. He was an amazing scientist, mentor and teacher.

Joe Normandin: His door was always open to all of us grad students. I remember stopping by his office many times to run experiments by him (and find out what I was doing wrong).

Pam Patterson: Just heard the incredibly sad news that one of my dissertation committee members, Timothy Bartness, has passed away. I am heartbroken by the news. He has influenced, and will continue to influence, every experiment I design (strong inference!!), every paper/grant I write (the art of if/then statements), and every presentation I give (EVERY line on a graph should have a purpose). I would not be the same scientist I am today without his mentorship, and I know I am not alone. Rest in peace, TJB. I know all of my fellow GSU neuro-peeps would agree: he will be missed.

The high standards to which he held himself had an amazing motivational effect on so many of us. Turned us all into little Bartnessites.

Amy Ross: So very true. I still ask myself quite often, “What would TJB do?”

Kyle Frantz: 1. Funnel from broad to narrow focus in the introduction; from narrow to broad in the discussion. So simple. 2. When colleagues acted up in faculty meetings, he’d comment “no GABA today, eh?”. Just two nuggets from Tim.

Ares Patrulis: Tim was truly one-of-a-kind scientist. He prized thinking outside of the box but in a supremely rigorous way. He believed in the question and not scientific fads and went after all of it with passion and verve. Absolutely fearless. He always had, and will continue to have, my full respect. I miss his voice terribly. This is true loss for neuroscience. I could say much more, but this will suffice.

Stephanie Josephine: My heart is heavy over this news. Tim played a huge role in my decision to attend GSU. I owe him a massive amount of gratitude for his willingness to serve on my committees, for giving constant feedback, and his overall incredible scientific inspiration. I have a lot of days where I question some of my career decisions or feel a semblance of bitterness for being overworked and underpaid (“the students don’t care,” I say! Yes, I know, “these kids today….” I say, as more and more of my hairs turn gray). At my dissertation defense, Tim asked me what I wanted to be when I grew up. I answered that I wanted to have a positive influence on undergraduate education, but I didn’t quite know how I was going to do that (I felt, at the time, like that was a terrible answer since I didn’t have a clear trajectory at the time.). I have to say looking at the beautiful memories people are sharing tonight about Tim as an educator and a person reminds me of why we do what we do. Students do care. We’ve all been positively influenced as scientists and people by Tim and it’s quite clear we’re all continuing to share his legacy. RIP TJB.

Dayne Loyd Averett: This is devastating news. I’ve read all of your comments and they are all so touching and funny, and anyone who worked will Tim can relate to each of your wonderful comments. I have never written a grant without hearing Tims voice critiquing the organization and writing. All my grants have the Bartness stamp, bolding, underlining and italicizing, all of it lol. It is obvious he has left a legacy in his alum.

From me (Jill Schneider): This is so bitter sweet to see the hard evidence of your goodness and how you have honored your teachers and blessed your students. They will surely carry on your legacy to places we can’t even imagine. Love you, my brother.

Best, me

(Tim also played the sax, and I think he would have liked you to hear this!)

Happy Fat Tuesday from Schneider Lab

As Fat Tuesday approaches, my mind turns to cycles of indulgence and moderation. This is not news to women. They are quite familiar with regular, repeated bouts of uncontrollable appetite. Women are more prone to obesity and binge eating, and their binges are more likely to occur at a certain phase of the menstrual cycle. These differences are related, at least in part, to changes in hormones secreted from the ovaries. The ovaries secrete steroid hormones, such as estradiol and progesterone. Changes in estradiol and progesterone secretion alter the steroid environment in the brain and body, so that when hunger strikes, we might feel “just peckish” at one stage of the menstrual cycle or ravenously hungry at another phase.

How does this work? I received a four-year research grant from the National Science Foundation in 2013 to study ovarian hormone effects on appetite.

One clue to understanding estradiol is that it affects sexual desire and hunger for food in the opposite direction. In the middle of the menstrual cycle, when estradiol levels are highest, the appetite for food falls to its lowest level. This is the time when females are most fertile and sexual desire peaks (although sexual activity can occur any time during the menstrual cycle). As women approach menstruation, progesterone levels and the appetite for food rise while sexual desire tends to fall. Similarly, after menopause, as the ovarian hormones wane so does sexual urgency (to different degrees, depending on the individual).

So, changes in hunger for food are correlated with changes ovarian steroid hormones, but correlations cannot tell you what causes what. My work started by looking for brain hormones secreted by cells with steroid receptors, brain hormones that increase the appetite for food and decrease the desire for sex. The problem is, we can’t really muck around in our own brains to study these hormones (neuropeptides). It’s difficult to study human food intake and sexual behavior because people lie about how much and what they eat. Don’t even get me started on measuring their sexual desire. No thanks. I like to study Syrian hamsters because I can precisely control what they eat, and they ovulate like clockwork every 4 days, unlike women who ovulate every 24-32 days. Plus, hamsters have a great way to demonstrate their hunger. After a period of dieting (say, we feed them only 75% of their normal daily food intake for a week), when we give them back their food, they increase their food hoarding. The hungrier they are the more food they carry in their cheek pouches from a distant source to their home cage. We can measure hamster sexual desire and hunger for food quite easily and accurately.

Hamster food hoarding (mean and s.e.m.) over the four days of the ovulatory cycle in food-restricted (open triangles, dotted lines) and food-unlimited (solid circles and lines) females housed with the choice between staying home, visiting a male, or hoarding food. The predominant sex behavior of the food-restricted female is shown in a cartoon above the hoarding data. On day 4 of the cycle, the periovulatory day, the females show mating behavior. On day 3, they show vaginal scent marking but do not mate. On days 1 and 2 they spend more time hoarding food than visiting the male. (Adapted from Klingerman et al., 2010 by Jay Alexander)

            Candice Klingerman (a former grad student in my lab at Lehigh University and now a real professor at Bloomsburg University), found that hamsters on calorie-restricting diets show little interest in males and spend most of their time busily hoarding food, except on the day of ovulation. As ovulation approaches, however, they spend more and more time near the males. What you might find surprising is unrestricted females are obsessed with males throughout the ovulatory cycle! Whether they are ovulating or not, they ignore the food and spend more than 75% of their time leaving vaginal scent marks near the males. Like most rodents, they mate only on the day of ovulation, but the chubbier, calorie-unrestricted females prefer males over food every day of their four-day cycle. The differences between the calorie-restricted and unrestricted females are illustrated in the graph to the right, where you can see that calorie-restricted females do lots of food hoarding on most days of the cycle, with a conspicuous dip at the time of ovulation. The unrestricted females’ hoarding levels are low and flat throughout the cycle because they spend most of their time with the male (Klingerman et al., 2010).

You can see from the figure above that living in an “all-you-can-eat” buffet masks the effects of the ovarian cycle on the appetites for food and sex. Females on the “all-you-can-eat” diet consistently prefer to court males rather than stock their larder with food. Those females that are calorie-limited save all their sexual ardor for the small window of fertility on the day of ovulation. They spend the rest of the ovulatory cycle busily hoarding food. In the wild, this would ensure that there will be plenty of energy available for their offspring if their mating results in a pregnancy. This result makes me wonder whether our understanding of sex hormones has been clouded by studying animals housed in small cages with unlimited food. It makes me wonder how much our own species has diverged from our ancestors, now that we have adopted a sedentary lifestyle with food available in office vending machines, coffee break rooms, fast food restaurants, and well-stocked homes. No wonder we sit around watching Game of Thrones.

What are the brain differences between the hamsters on a limited-calorie diet and the hamsters at the “all-you-can-eat” buffet? I suspected that I would be able to find a brain hormone (neuropeptide) secreted by cells that have steroid receptors. I further suspected that the secretion of this neuropeptide is increased by food restriction. A review of the literature revealed many such chemicals. I have posted a handy table in a previous blog post here.

At the moment, we are interested in gonadotropin inhibiting hormone, GnIH. The figure below shows a hamster brain cell (neuron) that produces GnIH (a neuropeptide), which is stained red. Those GnIH cells that were activated by food restriction are shown in red with a green/yellow dot in the middle. These are cells labeled for GnIH and Fos, a marker for cellular activation. I got interested in GnIH when my colleague, Lance Kriegsfeld at the University of California at Berkeley, showed that GnIH inhibits reproduction in Syrian hamsters.

Brain cells stained for GnIH (red) and Fos (green). The red stain represents GnIH which occurs in the cytoplasm and thus colors a wide area of the cell body. The greed stain represents the proto-oncogene product Fos, a protein that is synthesized upon cellular activation. Fos resides within the cell nucleus. Cells that are red with a green/yellow stained nucleus are double-labeled with GnIH and Fos. These represent GnIH-containing cells that have been activated by food restriction. (Photograph and immunohistochemistry by Noah Benton)

Some of my other great colleagues in Australia (e.g., Iain Clarke) were showing that GnIH increases food intake in sheep, monkeys, and rats. GnIH sounded promising. Thus, I approached Lance about studying the effects of GnIH on the appetites for food and sex in Syrian hamsters. My student Candice Klingerman partnered with a grad student from the Kriegsfeld lab, Wilbur P. Williams. Together, Klingerman and Williams found that the level of calorie restriction was a good predictor of the level of GnIH cell activation (Klingerman, Williams, et al., 2011).

           This suggested that GnIH might be part of the system that orchestrates the appetities for food and sex. This was confirmed by Noah Benton (Lehigh) and David Piekarski (UC-Berkeley). They administered GnIH to the brains of well fed females, and found that the GnIH-treated hamsters acted like they were starving. Their sexual appetites were lowered and their hunger for food was increased by GnIH treatment in the brain.

            Another prediction you can make based on the hoarding data shown above is that GnIH will have different effects depending on the day of the ovualtory cycle (and the levels of estradiol and progesterone secreted from the ovary). Consistent with this idea, my student Noah Benton is finding that in food-restricted females, the activity of GnIH is elevated only during the nonfertile periods of the female cycle. In the figure above, GnIH cells are shown in red, and the activation of those cells is indicated by the central dot stained green for Fos, a protein that shows up in cells that have been activated. Noah double-labeled cells for both Fos and GnIH in food-restricted and food-unlimited females on every day of the ovulatory cycle. On nonfertile days of the cycle, there are significantly more GnIH cells activated in food-restricted compared to food-unlimited females. As you would predict from their sexy behavior, however, on the day of ovulation, GnIH is not elevated by food restriction. Go, Noah!

GnIH activity is usually elevated in food-restricted females, except at ovulation. We think the effects of GnIH are dampened by one of the hormones that is high around the time of ovulation. Noah Benton’s dissertation work will determine which ovarian steroid hormones and receptor are important for these effects. Will it be estradiol, progesterone, or testosterone? Place your bets.

Many obesity researchers think that appetite suppressing hormones are suppose to function to preserve our youthful figures and keep our body weights in fashionable and healthy limits. The work of my students shows that an important function of these hormones is to orchestrate the appetites for food and sex, perhaps to maximize reproductive success in environments where energy availability fluctuates. These effects are short-lived and change rapidly in the small time window of fertility (basically 1 day of the 4-day ovulatory cycle). It is probably unrealistic to expect any one of these neuropeptides to be a long-term or permanent cure obesity. Maybe we should think more broadly about how all this obesity has come about, and put some energy into understanding the link between energy balance (food intake, body fat storage, and energy expenditure) and reproduction.

Meanwhile, enjoy Mardi Gras with some…